U.S. patent application number 14/116205 was filed with the patent office on 2014-04-10 for pyridyl aminopyridines as syk inhibitors.
The applicant listed for this patent is Michael D. Altman, Kaleen Konrad Childers, Maria Emilia Di Francesco, John Michael Ellis, Andrew M. Haidle, Alan B. Northrup, Ryan D. Otte, Liping Wang. Invention is credited to Michael D. Altman, Kaleen Konrad Childers, Maria Emilia Di Francesco, John Michael Ellis, Andrew M. Haidle, Alan B. Northrup, Ryan D. Otte, Liping Wang.
Application Number | 20140100250 14/116205 |
Document ID | / |
Family ID | 47139532 |
Filed Date | 2014-04-10 |
United States Patent
Application |
20140100250 |
Kind Code |
A1 |
Altman; Michael D. ; et
al. |
April 10, 2014 |
PYRIDYL AMINOPYRIDINES AS SYK INHIBITORS
Abstract
The present invention provides novel pyrimidine amines of
formula I which are potent inhibitors of spleen tyrosine kinase,
and are useful in the treatment and prevention of diseases mediated
by said enzyme, such as asthma, COPD, rheumatoid arthritis, and
cancer.
Inventors: |
Altman; Michael D.;
(Needham, MA) ; Di Francesco; Maria Emilia;
(Houston, TX) ; Haidle; Andrew M.; (Cambridge,
MA) ; Otte; Ryan D.; (Natick, MA) ; Ellis;
John Michael; (Needham, MA) ; Childers; Kaleen
Konrad; (Newton, MA) ; Northrup; Alan B.;
(Reading, MA) ; Wang; Liping; (Dayton,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Altman; Michael D.
Di Francesco; Maria Emilia
Haidle; Andrew M.
Otte; Ryan D.
Ellis; John Michael
Childers; Kaleen Konrad
Northrup; Alan B.
Wang; Liping |
Needham
Houston
Cambridge
Natick
Needham
Newton
Reading
Dayton |
MA
TX
MA
MA
MA
MA
MA
NJ |
US
US
US
US
US
US
US
US |
|
|
Family ID: |
47139532 |
Appl. No.: |
14/116205 |
Filed: |
May 4, 2012 |
PCT Filed: |
May 4, 2012 |
PCT NO: |
PCT/US2012/036426 |
371 Date: |
November 7, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61484431 |
May 10, 2011 |
|
|
|
Current U.S.
Class: |
514/333 ;
546/256 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 29/00 20180101; C07D 417/14 20130101; A61P 35/00 20180101;
A61P 37/00 20180101; A61P 43/00 20180101; A61P 11/06 20180101; A61P
19/02 20180101 |
Class at
Publication: |
514/333 ;
546/256 |
International
Class: |
C07D 417/14 20060101
C07D417/14 |
Claims
1. A compound having the formula I: ##STR00113## or a
pharmaceutically acceptable salt thereof, wherein A is a
carbocycle, or the moiety A-(R.sup.7).sub.n(R.sup.8) represents
##STR00114## n is 0, 1, 2 or 3; p and q are independently selected
from 1, 2 and 3; R.sup.1 is C.sub.1-4alkyl, C.sub.1-4fluoroalkyl,
C.sub.3-6cycloalkyl or C.sub.1-4alkoxy; R.sup.2 is H or halogen;
R.sup.3 is H, halogen, C.sub.1-4alkyl, C.sub.1-4haloalkyl,
C.sub.3-6cycloalkyl or C.sub.1-4hydroxyalkyl; R.sup.4 is H or
halogen; R.sup.5 is OH, C.sub.1-4alkoxy, halogen, NH.sub.2; or
N(H)(C.sub.1-4alkyl); R.sup.6 is H, C.sub.1-4alkyl,
C.sub.1-4haloalkyl, C.sub.3-6cycloalkyl or C.sub.1-4hydroxyalkyl;
or R.sup.7 is selected from OH and C.sub.1-4alkyl; R.sup.8 is
selected from (CR.sup.aR.sup.b).sub.nCO.sub.2R.sup.c,
CONR.sup.dR.sup.e, tetrazolyl, OH, CH.sub.2OH, oxo, CN,
NHCO.sub.2R.sup.f and NHSO.sub.2R.sup.f with the proviso that
R.sup.8 and --C(R.sup.5)(R.sup.6)-- are not attached to the same
ring carbon atom; R.sup.a and R.sup.b are each independently
selected from H and methyl; R.sup.c is H or C.sub.1-4alkyl, R.sup.d
and R.sup.e are each independently selected from H and
C.sub.1-4alkyl; and R.sup.f is C.sub.1-4alkyl or benzyl.
2. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein ring A is a carbocycle.
3. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein A is C.sub.3-6 cycloalkyl.
4. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein A is cyclohexyl.
5. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein R.sup.5 is OH.
6. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein A is a carbocycle, and R.sup.8 is selected from
(CR.sup.aR.sup.b).sub.nCO.sub.2R.sup.c and C(O)NR.sup.dR.sup.e.
7. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein A is C.sub.3-6cycloalkyl and R.sup.8 is
CO.sub.2R.sup.c.
8. The compound of claim 1 having the formula Ia: ##STR00115## or a
pharmaceutically acceptable salt thereof, wherein A is a
carbocycle; n is 0, 1 or 2; R.sup.1 is C.sub.1-4 alkyl or C.sub.1-4
fluoroalkyl; R.sup.3 is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl or
C.sub.3-6cycloalkyl; R.sup.6 is H, C.sub.1-4alkyl,
C.sub.1-4haloalkyl or C.sub.3-4cycloalkyl; R.sup.7 is C.sub.1-4
alkyl; R.sup.8 is CO.sub.2R.sup.c or CONR.sup.dR.sup.e; R.sup.c is
H or C.sub.1-4 alkyl, R.sup.d and R.sup.e are each independently
selected from H and C.sub.1-4alkyl.
9. The compound of claim 8 or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is C.sub.1-4 alkyl, C.sub.1-4 haloalkyl or
C.sub.3-6cycloalkyl; and R.sup.6 is H, C.sub.1-4alkyl, or
C.sub.1-4haloalkyl.
10. The compound of claim 1 having the formula Ib: ##STR00116## or
a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2;
R.sup.1 is C.sub.1-4 alkyl or C.sub.1-4fluoroalkyl; R.sup.3 is H,
C.sub.1-4alkyl, C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl; R.sup.6
is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl or C.sub.3-4cycloalkyl;
R.sup.7 is C.sub.1-4alkyl; R.sup.8 is CO.sub.2R.sup.c or
CONR.sup.dR.sup.e; R.sup.c is H or C.sub.1-4 alkyl, R.sup.d and
R.sup.e are each independently selected from H and
C.sub.1-4alkyl.
11. The compound of claim 10 or a pharmaceutically acceptable salt
thereof, wherein R.sup.8 is CO.sub.2R.sup.c.
12. The compound of claim 10 or a pharmaceutically acceptable salt
thereof, wherein R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl or
C.sub.3-6cycloalkyl; and R.sup.6 is H, C.sub.1-4alkyl or
C.sub.1-4haloalkyl.
13. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier.
14. A method for the treatment or prevention of Syk-mediated
diseases which comprises administering to a patient in need thereof
a therapeutically effective amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof.
15. The method of claim 14 wherein said disease is asthma or
COPD.
16. The method of claim 14 wherein said disease is rheumatoid
arthritis.
17. The method of claim 14 wherein said disease is cancer.
18. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] Spleen Tyrosine Kinase (Syk) is a protein tyrosine kinase
which has been described as a key mediator of immunoreceptor
signalling in a host of inflammatory cells including mast cells,
B-cells, macrophages and neutrophils. These immunoreceptors,
including Fc receptors and the B-cell receptor, are important for
both allergic diseases and antibody-mediated autoimmune diseases
and thus pharmacologically interfering with Syk could conceivably
treat these disorders.
[0002] Allergic rhinitis and asthma are diseases associated with
hypersensitivity reactions and inflammatory events involving a
multitude of cell types including mast cells, eosinophils, T cells
and dendritic cells. Following exposure to allergen, high affinity
immunoglobulin receptors for IgE and IgG become cross-linked and
activate downstream processes in mast cells and other cell types
leading to the release of pro-inflammatory mediators and airway
spasmogens. In the mast cell, for example, IgE receptor
cross-linking by allergen leads to release of mediators including
histamine from pre-formed granules, as well as the synthesis and
release of newly synthesized lipid mediators including
prostaglandins and leukotrienes.
[0003] Syk kinase is a non-receptor linked tyrosine kinase which is
important in transducing the downstream cellular signals associated
with cross-linking Fc.sub.epsilonR1 and or Fc.sub.epsilonR1
receptors, and is positioned early in the signaling cascade. In
mast cells, for example, the early sequence of Fc.sub.epsilonR1
signalling following allergen cross-linking of receptor-IgE
complexes involves first Lyn (a Src family tyrosine kinase) and
then Syk. Inhibitors of Syk activity would therefore be expected to
inhibit all downstream signalling cascades thereby alleviating the
immediate allergic response and adverse events initiated by the
release of pro-inflammatory mediators and spasmogens (Wong et al
2004, Expert Opin. Investig. Drugs (2004) 13 (7) 743-762).
[0004] Recently, it has been shown that the Syk kinase inhibitor
R112 (Rigel), dosed intranasally in a phase I/II study for the
treatment of allergic rhinitis, gave a statistically significant
decrease in PGD2, a key immune mediator that is highly correlated
with improvements in allergic rhinorrhea, as well as being safe
across a range of indicators, thus providing the first evidence for
the clinical safety and efficacy of a topical Syk kinase inhibitor.
(Meltzer, Eli O.; Berkowitz, Robert B.; Grossbard, Elliott B,
Journal of Allergy and Clinical Immunology (2005), 115(4),
791-796). In a more recent phase II clinical trial for allergic
rhinitis (Clinical Trials.gov Identifier NCT0015089), R112 was
shown as having a lack of efficacy versus placebo.
[0005] Rheumatoid Arthritis (RA) is an auto-immune disease
affecting approximately 1% of the population. It is characterised
by inflammation of articular joints leading to debilitating
destruction of bone and cartilage. Recent clinical studies with
Rituximab, which causes a reversible B cell depletion, (J. C. W.
Edwards et al 2004, New Eng. J. Med. 350: 2572-2581) have shown
that targeting B cell function is an appropriate therapeutic
strategy in auto-immune diseases such as RA. Clinical benefit
correlates with a reduction in auto-reactive antibodies (or
Rheumatoid Factor) and these studies suggest that B cell function
and indeed auto-antibody production are central to the ongoing
pathology in the disease.
[0006] Studies using cells from mice deficient in the Spleen
Tyrosine Kinase (Syk) have demonstrated a non-redundant role of
this kinase in B cell function. The deficiency in Syk is
characterised by a block in B cell development (M. Turner et al
1995 Nature 379: 298-302 and Cheng et al 1995, Nature 378:
303-306). These studies, along with studies on mature B cells
deficient in Syk (Kurasaki et al 2000, Immunol. Rev. 176:19-29),
demonstrate that Syk is required for the differentiation and
activation of B cells. Hence, inhibition of Syk in RA patients is
likely to block B cell function and thereby reduce Rheumatoid
Factor production. In addition to the role of Syk in B cell
function, and of further relevance to the treatment of RA, is the
requirement for Syk activity in Fc receptor (FcR) signalling. FcR
activation by immune complexes in RA has been suggested to
contribute to the release of multiple pro-inflammatory
mediators.
[0007] U.S. Pat. No. 7,803,801 discloses Syk inhibitors having the
formula:
##STR00001##
wherein the variables are as defined therein.
[0008] The present invention relates to novel compounds, which are
inhibitors of Syk kinase activity. These compounds therefore have
potential therapeutic benefit in the treatment of disorders
associated with inappropriate Syk activity, in particular in the
treatment and prevention of disease states mediated by Syk. Such
disease states may include inflammatory, allergic and autoimmune
diseases, for example, asthma, chronic obstructive pulmonary
disease (COPD), adult respiratory distress syndrome (ARDS),
ulcerative colitis, Crohns disease, bronchitis, dermatitis,
allergic rhinitis, psoriasis, scleroderma, urticaria, rheumatoid
arthritis, idiopathic thrombocytopenic purpura (ITP), multiple
sclerosis, cancer, HIV and lupus.
SUMMARY OF THE INVENTION
[0009] The present invention provides novel compounds that are
potent inhibitors of Syk as well as pharmaceutical compositions
containing them. As Syk inhibitors compounds of the present
invention are useful in the treatment and prevention of diseases
and disorders mediated by the Syk protein; such diseases and
disorders include, but are not limited to, asthma, COPD, rheumatoid
arthritis, cancer and idiopathic thrombocytopenic purpura.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The present invention provides compounds of formula I:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein A is a
carbocycle, or the moiety A-(R.sup.7).sub.n(R.sup.8) represents
##STR00003##
n is 0, 1, 2 or 3; p and q are independently selected from 1, 2 and
3; R.sup.1 is C.sub.1-4alkyl, C.sub.1-4fluoroalkyl,
C.sub.3-6cycloalkyl or C.sub.1-4alkoxy; R.sup.2 is H or halogen;
R.sup.3 is H, halogen, C.sub.1-4alkyl, C.sub.1-4haloalkyl,
C.sub.3-6cycloalkyl or C.sub.1-4 hydroxyalkyl; R.sup.4 is H or
halogen; R.sup.5 is OH, C.sub.1-4alkoxy, halogen, NH.sub.2; or
N(H)(C.sub.1-4alkyl); R.sup.6 is H, C.sub.1-4haloalkyl, C.sub.3-6
cycloalkyl or C.sub.1-4hydroxyalkyl; or R.sup.7 is selected from OH
and C.sub.1-4 alkyl; R.sup.8 is selected from
(CR.sup.aR.sup.b).sub.nCO.sub.2R.sup.c, CONR.sup.dR.sup.e,
tetrazolyl, OH, CH.sub.2OH, oxo, CN, NHCO.sub.2R.sup.f and
NHSO.sub.2R.sup.f; with the proviso that R.sup.8 and
C(R.sup.5)(R.sup.6) are not attached to the same ring carbon atom;
R.sup.a and R.sup.b are each independently selected from H and
methyl; R.sup.c is H or C.sub.1-4 alkyl, R.sup.d and R.sup.e are
each independently selected from H and C.sub.1-4alkyl; and R.sup.f
is C.sub.1-4alkyl or benzyl.
[0011] In one group of formula I are compounds wherein the ring A
is a carbocycle. In one subgroup thereof is selected from C.sub.3-6
cycloalkyl. In one embodiment A is selected from cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl. In a second embodiment A is
cyclohexyl.
[0012] In another group of formula I are compounds wherein R.sup.1
is C.sub.1-4alkyl or C.sub.1-4 fluoroalkyl. In one subgroup thereof
R.sup.1 is C.sub.1-3 alkyl, such as methyl, ethyl, n-propyl or
isopropyl. In a second subset thereof R.sup.1 is C.sub.1-3
fluoroalkyl such as difluoromethyl or trifluoromethyl. In one
embodiment R.sup.1 is methyl. In a second embodiment R.sup.1 is
trifluoromethyl. In a third embodiment R.sup.1 is cyclopropyl.
[0013] In another group of formula I are compounds wherein R.sup.2
is H or F.
[0014] In another group of formula I are compounds wherein R.sup.3
is C.sub.1-4 alkyl, C.sub.1-4 haloalkyl or C.sub.3-6cycloalkyl. In
one subgroup thereof R.sup.3 is C.sub.1-4alkyl,
C.sub.1-4fluoroalkyl or C.sub.3-6 cycloalkyl. In one embodiment
R.sup.3 is selected from methyl, difluoromethyl and cyclopropyl. In
a second embodiment R.sup.3 is methyl.
[0015] In another group of formula I are compounds wherein R.sup.5
is OH, C.sub.1-4 alkoxy, halogen, or NH.sub.2. In one embodiment
R.sup.5 is OH.
[0016] In another group of formula I are compounds wherein R.sup.6
is H, C.sub.1-4alkyl or C.sub.1-4 haloalkyl. In one subgroup
thereof R.sup.6 is H, C.sub.1-4 alkyl or C.sub.1-4 fluoroalkyl. In
another subgroup thereof R.sup.6 is selected from H, C.sub.1-3alkyl
and fluoro-, difluoro- and trifluoromethyl. In one embodiment
R.sup.6 is methyl.
[0017] In another group of formula I are compounds wherein A is a
carbocycle, and R.sup.8 is selected from
(CR.sup.aR.sup.b).sub.nCO.sub.2R.sup.c and C(O)NR.sup.dR.sup.e. In
one subgroup thereof R.sup.8 is selected from CO.sub.2R.sup.c and
C(O)NR.sup.dR.sup.e. In one embodiment A is C.sub.3-6 cycloalkyl
and R.sup.8 is CO.sub.2Re. In a second embodiment A is C.sub.3-6
cycloalkyl and R.sup.8 is C(O)NR.sup.dR.sup.e.
[0018] In another group of formula I are compounds having the
formula Ia:
##STR00004##
or a pharmaceutically acceptable salt thereof, wherein A is a
carbocycle; n is 0, 1 or 2; R.sup.1 is C.sub.1-4alkyl or
C.sub.1-4fluoroalkyl; R.sup.3 is H, C.sub.1-4alkyl,
C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl; R.sup.6 is H,
C.sub.1-4alkyl or C.sub.1-4haloalkyl; R.sup.7 is
C.sub.1-4alkyl;
R.sup.8 is CO.sub.2Re or CONR.sup.dR.sup.e;
[0019] R.sup.c is H or C.sub.1-4alkyl, R.sup.d and R.sup.e are each
independently selected from H and C.sub.1-4alkyl.
[0020] In one group of formula Ia, R.sup.3 is C.sub.1-4alkyl,
C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl. In another group
thereof, R.sup.3 is H, C.sub.1-4alkyl, C.sub.1-4fluoroalkyl or
C.sub.3-6cycloalkyl. In another group, R.sup.3 is H, methyl,
difluoromethyl, and cyclopropyl. In one embodiment R.sup.3 is H or
methyl.
[0021] In another group of formula Ia, R.sup.6 is H, C.sub.1-4
alkyl, C.sub.1-4 fluoroalkyl or C.sub.3-4cycloalkyl.
[0022] In another group of formula Ia, R.sup.3 is C.sub.1-4alkyl,
C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl; and
[0023] R.sup.6 is H, C.sub.1-4alkyl, or C.sub.1-4haloalkyl.
[0024] In another group of formula I are compounds having the
formula Ib:
##STR00005##
or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or
2; R.sup.1 is C.sub.1-4alkyl or C.sub.1-4fluoroalkyl; R.sup.3 is
C.sub.1-4 alkyl, C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl; R.sup.6
is H, C.sub.1-4alkyl or C.sub.1-4haloalkyl; R.sup.7 is C.sub.1-4
alkyl;
R.sup.8 is CO.sub.2R.sup.c or CONR.sup.dR.sup.e;
[0025] R.sup.c is H or C.sub.1-4alkyl, R.sup.d and R.sup.e are each
independently selected from H and C.sub.1-4alkyl.
[0026] In one group of formula Ib, R.sup.3 is C.sub.1-4alkyl,
C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl. In another group
thereof, R.sup.3 is H, C.sub.1-4alkyl, C.sub.1-4fluoroalkyl or
C.sub.3-6cycloalkyl. In another group, R.sup.3 is H, methyl,
difluoromethyl, and cyclopropyl. In one embodiment R.sup.3 is H or
methyl.
[0027] In another group of formula Ib, R.sup.6 is H,
C.sub.1-4alkyl, C.sub.1-4fluoroalkyl or C.sub.3-4cycloalkyl.
[0028] In another group of formula Ib, R.sup.3 is C.sub.1-4alkyl,
C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl; and
[0029] R.sup.6 is H, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl.
[0030] In certain embodiments of the compounds having the formula
Ib, the moiety
##STR00006##
has the configuration
##STR00007##
[0031] Representative compounds of the present invention are as
follows, where each named compound is intended to encompass its
individual isomers, mixtures thereof (including racemates and
diastereomeric mixtures), as well as pharmaceutically acceptable
salts thereof: [0032]
trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-
-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic acid;
[0033]
trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-
-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxamide; [0034]
trans-4-[1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3--
thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid; [0035]
trans-4-{1-hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridi-
n-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid; [0036]
butyl
trans-4-[1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-
-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate;
[0037]
trans-4-[1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-methylpyridine-
-2-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid;
[0038]
1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,-
3-thiazol-2-yl]-1-(pyrrolidin-3-yl)ethanol; and [0039]
3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyr-
idin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxamide. [0040]
trans-4-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]ami-
no}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid
[0041]
trans-4-[1-hydroxy-1-(5-{4-methyl-6-[(4-methylpyridin-2-yl)amino]pyridin--
2-yl}-1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylic acid [0042]
butyl
trans-4-[1-hydroxy-1-(5-{6-[(4-methoxypyridin-2-yl)amino]-4-methylpyridin-
-2-yl}-1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate [0043]
trans-4-[1-hydroxy-1-(5-{6-[(4-methoxypyridin-2-yl)amino]-4-methylpyridin-
-2-yl}-1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylic acid [0044]
trans-4-{1-[5-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridin--
2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}cyclohexanecarboxylic acid
[0045]
trans-4-[1-(5-{6-[(5-chloro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-
-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid
[0046] butyl
trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-
-2-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate
[0047]
trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-
-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid [0048]
trans-4-{1-hydroxy-1-[5-(4-methyl-6-{[4-(propan-2-yl)pyridin-2-yl]amino}p-
yridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid
[0049]
trans-4-[1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-
-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid
[0050]
3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyr-
idin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclopentanecarboxylic acid
[0051]
trans-4-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]ami-
no}pyridin-2-yl)-1,3-thiazol-2-yl]propyl}cyclohexanecarboxylic acid
[0052]
trans-4-{cyclopropyl(hydroxy)[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin--
2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]methyl}cyclohexanecarboxylic
acid [0053]
trans-4-{2,2,2-trifluoro-1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)-
pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxy-
lic acid [0054]
trans-4-{1-hydroxy-1-[5-(4-methyl-6-{[4-(propan-2-yloxy)pyridin-2-yl]amin-
o}pyridin-2-yl)-1,3-thiazol-2-yl]propyl}cyclohexanecarboxylic acid
[0055]
trans-4-{cyclopropyl(hydroxy)[5-(4-methyl-6-{[4-(propan-2-yloxy)pyridin-2-
-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]methyl}cyclohexanecarboxylic
acid [0056]
trans-4-{2,2,2-trifluoro-1-hydroxy-1-[5-(4-methyl-6-{[4-(propan-2--
yloxy)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanec-
arboxylic acid [0057] methyl
trans-4-{hydroxy[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]methyl}cyclohexanecarboxylate [0058]
trans-4-{hydroxy[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]methyl}cyclohexanecarboxylic acid
[0059]
(1S,4R)-4-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]a-
mino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}-2,2-dimethylcyclohexanecarboxyl-
ic acid [0060]
(1S,4S)-4-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]a-
mino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}-2,2-dimethylcyclohexanecarboxyl-
ic acid [0061]
(1S,4S)-4-[1-hydroxy-1-(5-{4-methyl-6-[(4-methylpyridin-2-yl)amino]pyridi-
n-2-yl}-1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohexanecarboxylic
acid [0062]
(1S,4S)-4-[1-hydroxy-1-(5-{6-[(4-methoxypyridin-2-yl)amino]-4-meth-
ylpyridin-2-yl}-1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohexanecarboxylic
acid [0063]
(1S,4S)-4-{1-[5-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridi-
n-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}-2,2-dimethylcyclohexanecarboxyli-
c acid [0064]
trans-4-[1-hydroxy-1-(5-{6-[(4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-
-thiazol-2-yl)ethyl]cyclohexanecarboxylic acid [0065]
trans-4-[1-hydroxy-1-(5-{6-[(4-methoxypyridin-2-yl)amino]pyridin-2-yl}-1,-
3-thiazol-2-yl)ethyl]cyclohexanecarboxylic acid [0066]
trans-4-{1-[5-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-
-thiazol-2-yl]-1-hydroxyethyl}cyclohexanecarboxylic acid [0067]
trans-4-{1-hydroxy-1-[5-(6-{[4-(propan-2-yl)pyridin-2-yl]amino}pyridin-2--
yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid [0068]
(1S,4S)-4-{1-hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyri-
din-2-yl)-1,3-thiazol-2-yl]ethyl}-2,2-dimethylcyclohexanecarboxylic
acid [0069]
(1S,4S)-4-[1-hydroxy-1-(5-{6-[(4-methylpyridin-2-yl)amino]pyridin--
2-yl}-1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohexanecarboxylic
acid [0070]
(1S,4S)-4-[1-hydroxy-1-(5-{6-[(4-methoxypyridin-2-yl)amino]pyridin-
-2-yl}-1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohexanecarboxylic
acid [0071]
(1S,4S)-4-{1-[5-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}pyridin--
2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl)-2,2-dimethylcyclohexanecarboxylic
acid [0072]
trans-4-{1-[5-(4-chloro-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-
-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}cyclohexanecarboxylic acid
[0073]
trans-4-{1-[5-(4-(difluoromethyl)-6-{[4-(trifluoromethyl)pyridin-2-yl]ami-
no}pyridin-2-yl]-1,3-thiazol-2-yl}-1-hydroxyethyl)cyclohexanecarboxylic
acid [0074]
trans-4-{1-[5-(4-cyclopropyl-6-[4-(trifluoromethyl)pyridin-2-yl]amino}pyr-
idin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}cyclohexanecarboxylic
acid [0075]
(4R)-4-{(1S)-1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyrid-
in-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidin-2-one
[0076]
(4R)-4-{(1R)-1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl-
]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidin-2-one [0077]
4-{1-hydroxy-1-[5-(4-methyl-6-[4-(trifluoromethyl)pyridin-2-yl]amino}pyri-
din-2-yl)-1,3-thiazol-2-yl]ethyl)-2-methylcyclohexanecarboxylic
acid
[0078] In another embodiment, the compounds (including
pharmaceutically acceptable salts thereof) are selected from the
following compounds: [0079]
trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridi-
n-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic
acid; [0080]
trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridi-
n-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxamide;
[0081]
cis-4-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino-
)pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid;
[0082]
trans-4-[1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3--
thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid; [0083]
trans-4-{1-hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridi-
n-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid; [0084]
butyl
trans-4-[1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-
-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate;
[0085]
trans-4-[1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-methylpyridine-
-2-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid;
[0086]
1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,-
3-thiazol-2-yl]-1-(pyrrolidin-3-yl)ethanol; and [0087]
3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyr-
idin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxamide.
[0088] In another embodiment, the compounds (including
pharmaceutically acceptable salts thereof) are selected from the
following compounds: [0089]
trans-4-[(1R)-1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylp-
yridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic
acid; [0090]
trans-4-[(1S)-1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylp-
yridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic
acid; [0091]
trans-4-[(1R)-1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylp-
yridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxamide;
[0092]
trans-4-[(1S)-1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylp-
yridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxamide;
[0093]
trans-4-{(1R)-1-Hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyri-
din-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic
acid; [0094]
trans-4-{(1S)-1-Hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-y-
l]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic
acid; [0095]
trans-4-[(1R)-1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]pyridi-
n-2-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic
acid; [0096]
trans-4-[(1S)-1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]pyridi-
n-2-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic
acid; [0097]
trans-4-{(1R)-1-Hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]-
amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic
acid; [0098]
trans-4-{(1S)-1-Hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]-
amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic
acid; [0099]
trans-4-[(1R)-1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-me-
thylpyridine-2-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic
acid; and [0100]
trans-4-[(1S)-1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-methylpyr-
idine-2-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic
acid.
[0101] In the application various terms are as defined below,
unless otherwise specified:
[0102] "Alkyl" refers to a straight- or branched-chain hydrocarbon
radical having the specified number of carbon atoms. Examples of
"alkyl" include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the
like.
[0103] "Carbocycle" refers to a non-aromatic saturated or partially
unsaturated monocyclic ring in which all ring atoms are carbon, and
the ring being isolated or fused (including ortho-fused,
Spiro-fused and bridged) to one or two such ring or to a benzene
ring. In the case of a polycyclic carbocycle, the attachment point
may be on any ring. Examples of carbocycles include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclohexenyl, cycloheptyl, cycloheptenyl, bicyclo[3.3.0]octane,
indane, bicyclo[3.3.1]nonane, decalin, tetrahydronaphthalene,
spiro[3.3]heptane, bicyclo[3.1.0]hexane, adamantane,
tricyclo[2.2.1.0.sup.2,6]heptane, dispiro[2.1.2.3]decane.
[0104] "Cycloalkyl" refers to a saturated ring containing the
specified number of ring carbon atoms, and no heteroatom. In a like
manner the term "C.sub.3-6 cycloalkyl" refers to a saturated ring
having from 3 to 6 ring carbon atoms. Exemplary "cycloalkyl" groups
useful in the present invention include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0105] "Halogen" or "halo" refers to fluorine, chlorine, bromine,
or iodine.
[0106] "Haloalkyl" refers to an alkyl group as defined above in
which one and up to all hydrogen atoms are replaced by a halogen;
halogen is as defined herein. Examples of such branched or straight
chained haloalkyl groups useful in the present invention include,
but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl
and n-butyl substituted independently with one or more halos, e.g.,
fluoro, chloro, bromo and iodo. Examples of "haloalkyl" include,
but are not limited to, fluoromethyl, difluoromethyl,
trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,
2,2,2-trifluoroethyl, and perfluoro-n-propyl.
[0107] "Hydroxyalkyl" refers to an alkyl group as defined above in
which one hydrogen on each carbon atom may be replaced by a hydroxy
group. Examples of "hydroxyalkyl" include, but are not limited to,
hydroxymethyl, hydroxyethyl, propane-1,2-diol.
[0108] The term "composition", as in pharmaceutical composition, is
intended to encompass a product comprising the active
ingredient(s), and the inert ingredient(s) (pharmaceutically
acceptable excipients) that make up the carrier, as well as any
product which results, directly or indirectly, from combination,
complexation or aggregation of any two or more of the ingredients,
or from dissociation of one or more of the ingredients, or from
other types of reactions or interactions of one or more of the
ingredients. Accordingly, the pharmaceutical compositions of the
present invention encompass any composition made by admixing a
compound of formula I, and pharmaceutically acceptable
excipients.
[0109] As used herein, the term "optionally" means that the
subsequently described event(s) may or may not occur, and includes
both event(s), which occur, and events that do not occur.
[0110] As used herein, the term "substituted with one or more
groups" refers to substitution with the named substituent or
substituents, multiple degrees of substitution, up to replacing all
hydrogen atoms with the same or different substituents, being
allowed unless the number of substituents is explicitly stated.
Where the number of substituents is not explicitly stated, one or
more is intended.
[0111] Each variable is independently defined each time it occurs
within the generic structural formula definitions. For example,
when there is more than one R.sup.7 substituents on the "A" ring,
each substituent is independently selected at each occurrence, and
each substituent can be the same or different from the
other(s).
[0112] The term "Syk inhibitor", is used to mean a compound which
inhibits the Syk enzyme.
[0113] The term "Syk mediated disease" or a "disorder or disease or
condition mediated by inappropriate Syk activity" is used to mean
any disease state mediated or modulated by Syk kinase mechanisms.
Such disease states may include inflammatory, allergic and
autoimmune diseases, for example, asthma, chronic obstructive
pulmonary disease (COPD), adult respiratory distress syndrome
(ARDs), ulcerative colitis, Crohns disease, bronchitis, dermatitis,
allergic rhinitis, psorasis, scleroderma, urticaria, rheumatoid
arthritis, multiple sclerosis, cancer, HW and lupus, in particular,
asthma, chronic obstructive pulmonary disease (COPD), adult
respiratory distress syndrome (ARDs), allergic rhinitis and
rheumatoid arthritis.
[0114] As used herein, "a compound of the invention" means a
compound of formula I or a salt, solvate or physiologically
functional derivative thereof.
[0115] As used herein, the term "solvate" refers to a complex of
variable stoichiometry formed by a solute (in this invention, a
compound of formula I, or a salt thereof) and a solvent. Such
solvents for the purpose of the invention may not interfere with
the biological activity of the solute. Examples of suitable
solvents include, but are not limited to, water, acetone, methanol,
ethanol and acetic acid. Preferably the solvent used is a
pharmaceutically acceptable solvent. Examples of suitable
pharmaceutically acceptable solvents include water, ethanol and
acetic acid. Most preferably the solvent is water.
[0116] As used herein, the term "physiologically functional
derivative" refers to a compound (e.g., a drug precursor) that is
transformed in vivo to yield a compound of formula I or a
pharmaceutically acceptable salt, hydrate or solvate of the
compound. The transformation may occur by various mechanisms (e.g.,
by metabolic or chemical processes), such as, for example, through
hydrolysis in blood. Prodrugs are such derivatives, and a
discussion of the use of prodrugs is provided by T. Higuchi and W.
Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the
A.C.S. Symposium Series, and in Bioreversible Carriers in Drug
Design, ed. Edward B. Roche, American Pharmaceutical Association
and Pergamon Press, 1987.
[0117] The compounds of formula I may have the ability to
crystallize in more than one form, a characteristic known as
polymorphism, and it is understood that such polymorphic forms
("polymorphs") are within the scope of formula I. Polymorphism
generally can occur as a response to changes in temperature or
pressure or both and can also result from variations in the
crystallization process. Polymorphs can be distinguished by various
physical characteristics known in the art such as x-ray diffraction
patterns, solubility and melting point.
[0118] The compounds of formula I may contain asymmetric or chiral
centers, and, therefore, exist in different stereoisomeric forms.
It is intended that all stereoisomeric forms of the compounds of
formula I as well as mixtures thereof, including racemic mixtures,
form part of the present invention. Diastereomeric mixtures can be
separated into their individual diastereomers on the basis of their
physical chemical differences by methods well known to those
skilled in the art, such as, for example, by chromatography and/or
fractional crystallization. Enantiomers can be separated by
converting the enantiomeric mixture into a diastereomeric mixture
by reaction with an appropriate optically active compound (e.g.,
chiral auxiliary such as a chiral alcohol or Mosher's acid
chloride), separating the diastereomers and converting (e.g.,
hydrolyzing) the individual diastereomers to the corresponding pure
enantiomers. Enantiomers can also be separated by chromatography
employing columns with a chiral stationary phase. Also, some of the
compounds of formula I may be atropisomers (e.g., substituted
biaryls) and are considered as part of this invention.
[0119] It is also noted that the compounds of formula I may form
tautomers. It is understood that all tautomers and mixtures of
tautomers of the compounds of the present invention are included
within the scope of the compounds of the present invention. Some of
the compounds described herein contain olefinic double bonds, and
unless specified otherwise, are meant to include both E and Z
geometric isomers.
[0120] Whilst the embodiments for each variable have generally been
listed above separately for each variable, this invention also
includes those compounds in which several or each embodiment in
formula I is selected from each of the embodiments listed above.
Therefore, this invention is intended to include all combinations
of embodiments for each variable.
[0121] The compounds of the present invention may be in the form of
and/or may be administered as a pharmaceutically acceptable salt.
For a review on suitable salts see Berge et al, J. Pharm. Sci.
1977, 66, 1-19. Typically, the salts of the present invention are
pharmaceutically acceptable salts. Salts encompassed within the
term "pharmaceutically acceptable salts" refer to non-toxic salts
of the compounds of this invention. Suitable pharmaceutically
acceptable salts can include acid or base additions salts.
[0122] A pharmaceutically acceptable acid addition salt can be
formed by reaction of a compound of formula I with a suitable
inorganic or organic acid (such as hydrobromic, hydrochloric,
sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic,
propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic,
glutamic, aspartic, p-toluenesulfonic, benzenesulfonic,
methanesulfonic, ethanesulfonic, naphthalenesulfonic such as
2-naphthalenesulfonic, or hexanoic acid), optionally in a suitable
solvent such as an organic solvent, to give the salt which is
usually isolated, for example, by crystallisation and filtration. A
pharmaceutically acceptable acid addition salt of a compound of
formula I can comprise or be, for example, a hydrobromide,
hydrochloride, sulfate, nitrate, phosphate, succinate, maleate,
formarate, acetate, propionate, fumarate, citrate, tartrate,
lactate, benzoate, salicylate, glutamate, aspartate,
p-toluenesulfonate, benzenesulfonate, methanesulfonate,
ethanesulfonate, naphthalenesulfonate (e.g.,
2-naphthalenesulfonate) or hexanoate salt.
[0123] A pharmaceutically acceptable base salt can be formed by
reaction of a compound of formula I with a suitable inorganic or
organic base. Salts derived from inorganic bases include aluminum,
ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,
manganic salts, manganous, potassium, sodium, zinc, and the like.
Particularly preferred are the ammonium, calcium, magnesium,
potassium, and sodium salts. Salts derived from pharmaceutically
acceptable organic non-toxic bases include salts of primary,
secondary, and tertiary amines, substituted amines including
naturally occurring substituted amines, cyclic amines, and basic
ion exchange resins, such as arginine, betaine, caffeine, choline,
N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine,
N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine,
purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine, and the like.
[0124] Other, non-pharmaceutically acceptable, salts, e.g.,
oxalates or trifluoroacetates, may also be used, for example, in
the isolation of compounds of the invention, and are included
within the scope of this invention.
[0125] The invention includes within its scope all possible
stoichiometric and non-stoichiometric forms of the compounds of
formula I.
[0126] In the compounds of formula I, the atoms may exhibit their
natural isotopic abundances, or one or more of the atoms may be
artificially enriched in a particular isotope having the same
atomic number, but an atomic mass or mass number different from the
atomic mass or mass number predominantly found in nature. The
present invention is meant to include all suitable isotopic
variations of the compounds of generic formula I. For example,
different isotopic forms of hydrogen (H) include protium (.sup.1H)
and deuterium (.sup.2H). Protium is the predominant hydrogen
isotope found in nature. Enriching for deuterium may afford certain
therapeutic advantages, such as increasing in vivo half-life or
reducing dosage requirements, or may provide a compound useful as a
standard for characterization of biological samples.
Isotopically-enriched compounds within generic formula I can be
prepared without undue experimentation by conventional techniques
well known to those skilled in the art or by processes analogous to
those described in the Schemes and Examples herein using
appropriate isotopically-enriched reagents and/or intermediates
[0127] The compounds of formula I and salts, solvates and
physiologically functional derivatives thereof are believed to be
inhibitors of Syk activity, and thus be potentially useful in the
treatment of diseases and conditions associated with inappropriate
Syk activity.
[0128] Compound of formula I or its pharmaceutically acceptable
salts and pharmaceutical compositions can be used to treat or
prevent a variety of conditions or diseases mediated by Spleen
tyrosine kinase (Syk). Such conditions and diseases include, but
are not limited to: (1) arthritis, including rheumatoid arthritis,
juvenile arthritis, psoriatic arthritis and osteoarthritis; (2)
asthma and other obstructive airways diseases, including chronic
asthma, late asthma, airway hyper-responsiveness, bronchitis,
bronchial asthma, allergic asthma, intrinsic asthma, extrinsic
asthma, dust asthma, adult respiratory distress syndrome, recurrent
airway obstruction, and chronic obstruction pulmonary disease
including emphysema; (3) autoimmune diseases or disorders,
including those designated as single organ or single cell-type
autoimmune disorders, for example Hashimoto's thyroiditis,
autoimmune hemolytic anemia, autoimmune atrophic gastritis of
pernicious anemia, autoimmune encephalomyelitis, autoimmune
orchitis, Goodpasture's disease, autoimmune thrombocytopenia
including idiopathic thrombopenic purpura, sympathetic ophthalmia,
myasthenia gravis, Graves' disease, primary biliary cirrhosis,
chronic aggressive hepatitis, ulcerative colitis and membranous
glomerulopathy, those designated as involving systemic autoimmune
disorder, for example systemic lupus erythematosis, immune
thrombocytopenic purpura, rheumatoid arthritis, Sjogren's syndrome,
Reiter's syndrome, polymyositis-dermatomyositis, systemic
sclerosis, polyarteritis nodosa, multiple sclerosis and bullous
pemphigoid, and additional autoimmune diseases, which can be B-cell
(humoral) based or T-cell based, including Cogan's syndrome,
ankylosing spondylitis, Wegener's granulomatosis, autoimmune
alopecia, Type I or juvenile onset diabetes, and thyroiditis; (4)
cancers or tumors, including alimentary/gastrointestinal tract
cancer, colon cancer, liver cancer, skin cancer including mast cell
tumor and squamous cell carcinoma, breast and mammary cancer,
ovarian cancer, prostate cancer, lymphoma and leukemia (including
but not limited to acute myelogenous leukemia, chronic myelogenous
leukemia, mantle cell lymphoma, NHL B cell lymphomas (e.g.,
precursor B-ALL, marginal zone B cell lymphoma, chronic lymphocytic
leukemia, diffuse large B cell lymphoma, Burkitt lymphoma,
mediastinal large B-cell lymphoma), Hodgkin lymphoma, NK and T cell
lymphomas; TEL-Syk and ITK-Syk fusion driven tumors) myelomas
including multiple myeloma, myeloproliferative disorders kidney
cancer, lung cancer, muscle cancer, bone cancer, bladder cancer,
brain cancer, melanoma including oral and metastatic melanoma,
Kaposi's sarcoma, proliferative diabetic retinopathy, and
angiogenic-associated disorders including solid tumors, and
pancreatic cancer; (5) diabetes, including Type I diabetes and
complications from diabetes; (6) eye diseases, disorders or
conditions including autoimmune diseases of the eye,
keratoconjunctivitis, vernal conjunctivitis, uveitis including
uveitis associated with Behcet's disease and lens-induced uveitis,
keratitis, herpetic keratitis, conical keratitis, corneal
epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's
ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada
syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule,
iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic
ophthalmitis, allergic conjunctivitis, and ocular
neovascularization; (7) intestinal inflammations, allergies or
conditions including Crohn's disease and/or ulcerative colitis,
inflammatory bowel disease, coeliac diseases, proctitis,
eosinophilic gastroenteritis, and mastocytosis; (8)
neurodegenerative diseases including motor neuron disease,
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, Huntington's disease, cerebral ischemia, or
neurodegenerative disease caused by traumatic injury, strike,
glutamate neurotoxicity or hypoxia; ischemic/reperfusion injury in
stroke, myocardial ischemica, renal ischemia, heart attacks,
cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ
hypoxia; (9) platelet aggregation and diseases associated with or
caused by platelet activation, such as arteriosclerosis,
thrombosis, intimal hyperplasia and restenosis following vascular
injury; (10) conditions associated with cardiovascular diseases,
including restenosis, acute coronary syndrome, myocardial
infarction, unstable angina, refractory angina, occlusive coronary
thrombus occurring post-thrombolytic therapy or post-coronary
angioplasty, a thrombotically mediated cerebrovascular syndrome,
embolic stroke, thrombotic stroke, transient ischemic attacks,
venous thrombosis, deep venous thrombosis, pulmonary embolus,
coagulopathy, disseminated intravascular coagulation, thrombotic
thrombocytopenic purpura, thromboangiitis obliterans, thrombotic
disease associated with heparin-induced thrombocytopenia,
thrombotic complications associated with extracorporeal
circulation, thrombotic complications associated with
instrumentation such as cardiac or other intravascular
catheterization, intra-aortic balloon pump, coronary stent or
cardiac valve, conditions requiring the fitting of prosthetic
devices, and the like; (11) skin diseases, conditions or disorders
including atopic dermatitis, eczema, psoriasis, scleroderma,
pruritus and other pruritic conditions; (12) allergic reactions
including anaphylaxis, allergic rhinitis, allergic dermatitis,
allergic urticaria, angioedema, allergic asthma, or allergic
reaction to insect bites, food, drugs, or pollen; (13) transplant
rejection, including pancreas islet transplant rejection, bone
marrow transplant rejection, graft-versus-host disease, organ and
cell transplant rejection such as bone marrow, cartilage, cornea,
heart, intervertebral disc, islet, kidney, limb, liver, lung,
muscle, myoblast, nerve, pancreas, skin, small intestine, or
trachea, and xeno transplantation; (14) low grade scarring
including scleroderma, increased fibrosis, keloids, post-surgical
scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion
injury, and post-myocardial infarction.
[0129] The invention thus provides compounds of formula I and
salts, solvates and physiologically functional derivatives thereof
for use in therapy, and particularly in the treatment of diseases
and conditions mediated by inappropriate Syk activity. The
inappropriate Syk activity referred to herein is any Syk activity
that deviates from the normal Syk activity expected in a particular
mammalian subject. Inappropriate Syk activity may take the form of,
for instance, an abnormal increase in activity, or an aberration in
the timing and or control of Syk activity. Such inappropriate
activity may result then, for example, from overexpression or
mutation of the protein kinase leading to inappropriate or
uncontrolled activation.
[0130] In a further embodiment, the present invention is directed
to methods of regulating, modulating, or inhibiting Syk for the
prevention and/or treatment of disorders related to unregulated Syk
activity.
[0131] In a further embodiment, the present invention provides a
method of treatment of a mammal suffering from a disorder mediated
by Syk activity, which comprises administering to said mammal an
effective amount of a compound of formula I or a pharmaceutically
acceptable salt, solvate, or a physiologically functional
derivative thereof.
[0132] In a further embodiment, the present invention provides for
the use of a compound of formula I, or a pharmaceutically
acceptable salt or solvate thereof, or a physiologically functional
derivative thereof, in the preparation of a medicament for the
treatment of a disorder mediated by Syk activity.
[0133] In a further embodiment said disorder mediated by Syk
activity is asthma. In a further embodiment said disorder is
rheumatoid arthritis. In yet another embodiment, said disorder is
cancer. In a further embodiment said disorder is ocular
conjunctivitis.
[0134] Yet another aspect of the present invention provides a
method for treating diseases caused by or associated with Fc
receptor signaling cascades, including FceRI and/or FcgRI-mediated
degranulation as a therapeutic approach towards the treatment or
prevention of diseases characterized by, caused by and/or
associated with the release or synthesis of chemical mediators of
such Fc receptor signaling cascades or degranulation. In addition,
Syk is known to play a critical role in immunotyrosine-based
activation motif (ITAM) signaling, B cell receptor signaling, T
cell receptor signaling and is an essential component of integrin
beta (1), beta (2), and beta (3) signaling in neutrophils. Thus,
compounds of the present invention can be used to regulate Fc
receptor, ITAM, B cell receptor and integrin signaling cascades, as
well as the cellular responses elicited through these signaling
cascades. Non-limiting examples of cellular responses that may be
regulated or inhibited include respiratory burst, cellular
adhesion, cellular degranulation, cell spreading, cell migration,
phagocytosis, calcium ion flux, platelet aggregation and cell
maturation.
[0135] While it is possible that, for use in therapy, a compound of
formula I, as well as salts, solvates and physiological functional
derivatives thereof, may be administered as the raw chemical, it is
possible to present the active ingredient as a pharmaceutical
composition. Accordingly, the invention further provides a
pharmaceutical composition, which comprises a compound of formula I
and salts, solvates and physiological functional derivatives
thereof, and one or more pharmaceutically acceptable carriers,
diluents, or excipients. The compounds of the formula I and salts,
solvates and physiological functional derivatives thereof, are as
described above. The carrier(s), diluent(s) or excipient(s) must be
acceptable in the sense of being compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof. In accordance with another aspect of the invention there
is also provided a process for the preparation of a pharmaceutical
composition including admixing a compound of the formula I, or
salts, solvates and physiological functional derivatives thereof,
with one or more pharmaceutically acceptable carriers, diluents or
excipients.
[0136] Pharmaceutical compositions of the present invention may be
presented in unit dose forms containing a predetermined amount of
active ingredient per unit dose. Such a unit may contain, for
example, 5 .mu.g to 3 g, preferably 1 mg to 700 mg, more preferably
5 mg to 100 mg of a compound of the formula I, depending on the
condition being treated, the route of administration and the age,
weight and condition of the patient. Such unit doses may therefore
be administered more than once a day. Preferred unit dosage
compositions are those containing a daily dose or sub-dose (for
administration more than once a day), as herein above recited, or
an appropriate fraction thereof, of an active ingredient.
Furthermore, such pharmaceutical compositions may be prepared by
any of the methods well known in the pharmacy art.
[0137] Pharmaceutical compositions of the present invention may be
adapted for administration by any appropriate route, for example by
the oral (including buccal or sublingual), rectal, topical,
inhaled, nasal, ocular, or parenteral (including intravenous and
intramuscular) route. Such compositions may be prepared by any
method known in the art of pharmacy, for example by bringing into
association the active ingredient with the carrier(s) or
excipient(s). Dosage forms include tablets, troches, dispersions,
suspensions, solutions, capsules, creams, ointments, aerosols, and
the like.
[0138] In a further embodiment, the present invention provides a
pharmaceutical composition adapted for administration by the oral
route, for treating, for example, rheumatoid arthritis.
[0139] In a further embodiment, the present invention provides a
pharmaceutical composition adapted for administration by the nasal
route, for treating, for example, allergic rhinitis.
[0140] In a further embodiment, the present invention provides a
pharmaceutical composition adapted for administration by the
inhaled route, for treating, for example, asthma, COPD or ARDS.
[0141] In a further embodiment, the present invention provides a
pharmaceutical composition adapted for administration by the ocular
route, for treating, diseases of the eye, for example,
conjunctivitis.
[0142] In a further embodiment, the present invention provides a
pharmaceutical composition adapted for administration by the
parenteral (including intravenous) route, for treating, for
example, cancer.
[0143] Pharmaceutical compositions of the present invention which
are adapted for oral administration may be presented as discrete
units such as capsules or tablets; powders or granules; solutions
or suspensions in aqueous or non-aqueous liquids; edible foams or
whips; or oil-in-water liquid emulsions or water-in-oil liquid
emulsions.
[0144] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Powders are prepared by
comminuting the compound to a suitable fine size and mixing with a
similarly comminuted pharmaceutical carrier such as an edible
carbohydrate, as, for example, starch or mannitol. Flavoring,
preservative, dispersing and coloring agent can also be
present.
[0145] Capsules are made by preparing a powder mixture, as
described above, and filling formed gelatin sheaths. Glidants and
lubricants such as colloidal silica, talc, magnesium stearate,
calcium stearate or solid polyethylene glycol can be added to the
powder mixture before the filling operation. A disintegrating or
solubilizing agent such as agar-agar, calcium carbonate or sodium
carbonate can also be added to improve the availability of the
medicament when the capsule is ingested.
[0146] Moreover, when desired or necessary, suitable binders,
lubricants, disintegrating agents and coloring agents can also be
incorporated into the mixture. Suitable binders include starch,
gelatin, natural sugars such as glucose or beta-lactose, corn
sweeteners, natural and synthetic gums such as acacia, tragacanth
or sodium alginate, carboxymethylcellulose, polyethylene glycol,
waxes and the like. Lubricants used in these dosage forms include
sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like. Tablets are formulated, for example, by
preparing a powder mixture, granulating or slugging, adding a
lubricant and disintegrant and pressing into tablets. A powder
mixture is prepared by mixing the compound, suitably comminuted,
with a diluent or base as described above, and optionally, with a
binder such as carboxymethylcellulose, an aliginate, gelatin, or
polyvinyl pyrrolidone, a solution retardant such as paraffin, a
resorption accelerator such as a quaternary salt and/or an
absorption agent such as bentonite, kaolin or dicalcium phosphate.
The powder mixture can be granulated by wetting with a binder such
as syrup, starch paste, acacia mucilage or solutions of cellulosic
or polymeric materials and forcing through a screen. As an
alternative to granulating, the powder mixture can be run through
the tablet machine and the result is imperfectly formed slugs
broken into granules. The granules can be lubricated to prevent
sticking to the tablet forming dies by means of the addition of
stearic acid, a stearate salt, talc or mineral oil. The lubricated
mixture is then compressed into tablets. The compounds of the
present invention can also be combined with a free flowing inert
carrier and compressed into tablets directly without going through
the granulating or slugging steps. A clear or opaque protective
coating consisting of a sealing coat of shellac, a coating of sugar
or polymeric material and a polish coating of wax can be provided.
Dyestuffs can be added to these coatings to distinguish different
unit dosages.
[0147] Oral fluids such as solution, syrups and elixirs can be
prepared in dosage unit form so that a given quantity contains a
predetermined amount of the compound. Syrups can be prepared by
dissolving the compound in a suitably flavored aqueous solution,
while elixirs are prepared through the use of a non-toxic alcoholic
vehicle. Suspensions can be formulated by dispersing the compound
in a non-toxic vehicle. Solubilizers and emulsifiers such as
ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol
ethers, preservatives, flavor additive such as peppermint oil or
natural sweeteners or saccharin or other artificial sweeteners, and
the like can also be added.
[0148] Where appropriate, dosage unit compositions for oral
administration can be microencapsulated. The formulation can also
be prepared to prolong or sustain the release, for example, by
coating or embedding particulate material in polymers, wax or the
like.
[0149] The compounds of formula I, and salts, solvates and
physiological functional derivatives thereof, can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines.
[0150] The compounds of formula I and salts, solvates and
physiological functional derivatives thereof may also be delivered
by the use of monoclonal antibodies as individual carriers to which
the compound molecules are coupled. The compounds may also be
coupled with soluble polymers as targetable drug carriers. Such
polymers can include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the compounds may
be coupled to a class of biodegradable polymers useful in achieving
controlled release of a drug, for example, polylactic acid,
polyepsilon caprolactone, polyhydroxy butyric acid,
polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates
and cross-linked or amphipathic block copolymers of hydrogels.
[0151] Dosage forms for inhaled administration may conveniently be
formulated as aerosols or dry powders.
[0152] For compositions suitable and/or adapted for inhaled
administration, it is preferred that the compound or salt of
formula I is in a particle-size-reduced form, and more preferably
the size-reduced form is obtained or obtainable by micronisation.
The preferable particle size of the size-reduced (e.g., micronised)
compound or salt or solvate is defined by a D50 value of about 0.5
to about 10 microns (for example as measured using laser
diffraction).
[0153] Aerosol formulations, e.g., for inhaled administration, can
comprise a solution or fine suspension of the active substance in a
pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol
formulations can be presented in single or multidose quantities in
sterile form in a sealed container, which can take the form of a
cartridge or refill for use with an atomising device or inhaler.
Alternatively the sealed container may be a unitary dispensing
device such as a single dose nasal inhaler or an aerosol dispenser
fitted with a metering valve (metered dose inhaler) which is
intended for disposal once the contents of the container have been
exhausted.
[0154] Where the dosage form comprises an aerosol dispenser, it
preferably contains a suitable propellant under pressure such as
compressed air, carbon dioxide or an organic propellant such as a
hydrofluorocarbon (HFC). Suitable HFC propellants include
1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2-tetrafluoroethane. The
aerosol dosage forms can also take the form of a pump-atomiser. The
pressurised aerosol may contain a solution or a suspension of the
active compound. This may require the incorporation of additional
excipients e.g., co-solvents and/or surfactants to improve the
dispersion characteristics and homogeneity of suspension
formulations. Solution formulations may also require the addition
of co-solvents such as ethanol. Other excipient modifiers may also
be incorporated to improve, for example, the stability and/or taste
and/or fine particle mass characteristics (amount and/or profile)
of the formulation.
[0155] For pharmaceutical compositions suitable and/or adapted for
inhaled administration, it is preferred that the pharmaceutical
composition is a dry powder inhalable composition. Such a
composition can comprise a powder base such as lactose, glucose,
trehalose, mannitol or starch, the compound of formula I or salt or
solvate thereof (preferably in particle-size-reduced form, e.g., in
micronised form), and optionally a performance modifier such as
L-leucine or another amino acid, and/or metals salts of stearic
acid such as magnesium or calcium stearate. Preferably, the dry
powder inhalable composition comprises a dry powder blend of
lactose and the compound of formula I or salt thereof. The lactose
is preferably lactose hydrate e.g., lactose monohydrate and/or is
preferably inhalation-grade and/or fine-grade lactose. Preferably,
the particle size of the lactose is defined by 90% or more (by
weight or by volume) of the lactose particles being less than 1000
microns (micrometres) (e.g., 10-1000 microns e.g., 30-1000 microns)
in diameter, and/or 50% or more of the lactose particles being less
than 500 microns (e.g., 10-500 microns) in diameter. More
preferably, the particle size of the lactose is defined by 90% or
more of the lactose particles being less than 300 microns (e.g.,
10-300 microns e.g., 50-300 microns) in diameter, and/or 50% or
more of the lactose particles being less than 100 microns in
diameter. Optionally, the particle size of the lactose is defined
by 90% or more of the lactose particles being less than 100-200
microns in diameter, and/or 50% or more of the lactose particles
being less than 40-70 microns in diameter. It is preferable that
about 3 to about 30% (e.g., about 10%) (by weight or by volume) of
the particles are less than 50 microns or less than 20 microns in
diameter. For example, without limitation, a suitable
inhalation-grade lactose is E9334 lactose (10% fines) (Borculo Domo
Ingredients, Hanzeplein 25, 8017 J D Zwolle, Netherlands).
[0156] Optionally, in particular for dry powder inhalable
compositions, a pharmaceutical composition for inhaled
administration can be incorporated into a plurality of sealed dose
containers (e.g., containing the dry powder composition) mounted
longitudinally in a strip or ribbon inside a suitable inhalation
device. The container is rupturable or peel-openable on demand and
the dose of e.g., the dry powder composition can be administered by
inhalation via the device such as the DISKUS.RTM.
device(GlaxoSmithKline). Other dry powder inhalers are well known
to those of ordinary skill in the art, and many such devices are
commercially available, with representative devices including
Aerolizer.RTM. (Novartis), Airmax.TM. (WAX), ClickHaler.RTM.
(Innovata Biomed), Diskhaler.RTM. (GlaxoSmithKline), Accuhaler
(GlaxoSmithKline), Easyhaler.RTM. (Orion Pharma), Eclipse.TM.
(Aventis), FlowCaps.RTM. (Hovione), Handihalerilb (Boehringer
Ingelheim), Pulvinal.RTM. (Chiesi), Rotahaler.RTM.
(GlaxoSmithKline), SkyeHaler.TM. or Certihaler.TM. (SkyePharma),
Twisthaler.RTM. (Schering-Plough), Turbuhaler.RTM. (AstraZeneca),
Ultrahaler.RTM. (Aventis), and the like.
[0157] Dosage forms for ocular administration may be formulated as
solutions or suspensions with excipients suitable for ophthalmic
use.
[0158] Dosage forms for nasal administration may conveniently be
formulated as aerosols, solutions, drops, gels or dry powders.
[0159] Pharmaceutical compositions adapted for administration by
inhalation include fine particle dusts or mists, which may be
generated by means of various types of metered, dose pressurised
aerosols, nebulizers or insufflators.
[0160] For pharmaceutical compositions suitable and/or adapted for
intranasal administration, the compound of formula I or a
pharmaceutically acceptable salt or solvate thereof may be
formulated as a fluid formulation for delivery from a fluid
dispenser. Such fluid dispensers may have, for example, a
dispensing nozzle or dispensing orifice through which a metered
dose of the fluid formulation is dispensed upon the application of
a user-applied force to a pump mechanism of the fluid dispenser.
Such fluid dispensers are generally provided with a reservoir of
multiple metered doses of the fluid formulation, the doses being
dispensable upon sequential pump actuations. The dispensing nozzle
or orifice may be configured for insertion into the nostrils of the
user for spray dispensing of the fluid formulation into the nasal
cavity. A fluid dispenser of the aforementioned type is described
and illustrated in WO-A-2005/044354, the entire content of which is
hereby incorporated herein by reference. The dispenser has a
housing which houses a fluid discharge device having a compression
pump mounted on a container for containing a fluid formulation. The
housing has at least one finger-operable side lever which is
movable inwardly with respect to the housing to cam the container
upwardly in the housing to cause the pump to compress and pump a
metered dose of the formulation out of a pump stem through a nasal
nozzle of the housing. A particularly preferred fluid dispenser is
of the general type illustrated in FIGS. 30-40 of
WO-A-2005/044354.
[0161] The following are examples of representative pharmaceutical
dosage forms for the compounds of this invention:
TABLE-US-00001 Injectable Suspension (I.M.) mg/ml Compound of
formula I 10 Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0
Benzalkonium chloride 1.0 Water for injection to a total volume of
1 ml
TABLE-US-00002 Tablet mg/tablet Compound of formula I 25
Microcrystalline Cellulose 415 Providone 14.0 Pregelatinized Starch
43.5 Magnesium Stearate 2.5 500
TABLE-US-00003 Capsule mg/capsule Compound of formula I 25 Lactose
Powder 573.5 Magnesium Stearate 1.5 600
TABLE-US-00004 Inhalation Aerosol Per dose Compound of formula I
100 mcg Oleic Acid 5 mcg Ethanol 1 mg HFA 227
(1,1,1,2,3,3,3-heptafluoropropane) 75 mg
TABLE-US-00005 Dry Powder Inhalation Aerosol Per dose Compound of
formula I 100 mcg Lactose 12.5 mg
[0162] It will be appreciated that when the compound of the present
invention is administered in combination with other therapeutic
agents normally administered by the inhaled, intravenous, oral or
intranasal route, that the resultant pharmaceutical composition may
be administered by the same routes.
[0163] It should be understood that in addition to the ingredients
particularly mentioned above, the compositions may include other
agents conventional in the art having regard to the type of
formulation in question, for example those suitable for oral
administration may include flavouring agents.
[0164] A therapeutically effective amount of a compound of the
present invention will depend upon a number of factors including,
for example, the age and weight of the animal, the precise
condition requiring treatment and its severity, the nature of the
formulation, and the route of administration, and will ultimately
be at the discretion of the attendant physician or veterinarian.
However, an effective amount of a compound of formula I for the
treatment of diseases or conditions associated with inappropriate
Syk activity, will generally be in the range of 5 .mu.g to 100
mg/kg body weight of recipient (mammal) per day and more usually in
the range of 5 .mu.g to 10 mg/kg body weight per day. This amount
may be given in a single dose per day or more usually in a number
(such as two, three, four, five or six) of sub-doses per day such
that the total daily dose is the same. An effective amount of a
salt or solvate, thereof, may be determined as a proportion of the
effective amount of the compound of formula I per se.
[0165] Compounds of the present invention, and their salts and
solvates, and physiologically functional derivatives thereof, may
be employed alone or in combination with other therapeutic agents
for the treatment of diseases and conditions associated with
inappropriate Syk activity. Combination therapies according to the
present invention thus comprise the administration of at least one
compound of formula I or a pharmaceutically acceptable salt or
solvate thereof, or a physiologically functional derivative
thereof, and the use of at least one other pharmaceutically active
agent. The compound(s) of formula I and the other pharmaceutically
active agent(s) may be administered together or separately and,
when administered separately this may occur simultaneously or
sequentially in any order. The amounts of the compound(s) of
formula I and the other pharmaceutically active agent(s) and the
relative timings of administration will be selected in order to
achieve the desired combined therapeutic effect.
[0166] For the treatment of the inflammatory diseases, rheumatoid
arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and
allergic rhinitis a compound of formula I may be combined with one
or more other active agents such as: (1) TNF-.alpha. inhibitors
such as infliximab (Remicade.RTM.), etanercept (Enbrel.RTM.),
adalimumab (Humira.RTM.), certolizumab pegol (Cimzia.RTM.), and
golimumab (Simponi.RTM.); (2) non-selective COX-I/COX-2 inhibitors
(such as piroxicam, diclofenac, propionic acids such as naproxen,
flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such
as mefenamic acid, indomethacin, sulindac, etodolac, azapropazone,
pyrazolones such as phenylbutazone, salicylates such as aspirin);
(3) COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib,
valdecoxib and etoricoxib); (4) other agents for treatment of
rheumatoid arthritis including methotrexate, leflunomide,
sulfasalazine, azathioprine, cyclosporin, tacrolimus,
penicillamine, bucillamine, actarit, mizoribine, lobenzarit,
ciclesonide, hydroxychloroquine, d-penicillamine, aurothiomalate,
auranofin or parenteral or oral gold, cyclophosphamide,
Lymphostat-B, BAFF/APRIL inhibitors and CTLA-4-Ig or mimetics
thereof; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase
(5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP)
antagonist such as zileuton; (6) LTD4 receptor antagonist such as
zafirlukast, montelukast and pranlukast; (7) PDE4 inhibitor such as
roflumilast, cilomilast, AWD-12-281 (Elbion), and PD-168787
(Pfizer); (8) antihistaminic H1 receptor antagonists such as
cetirizine, levocetirizine, loratadine, desloratadine,
fexofenadine, astemizole, azelastine, levocabastine, olopatidine,
methapyrilene and chlorpheniramine; (9) .alpha.1- and
.alpha.2-adrenoceptor agonist vasoconstrictor sympathomimetic
agent, such as propylhexedrine, phenylephrine, phenylpropanolamine,
pseudoephedrine, naphazoline hydrochloride, oxymetazoline
hydrochloride, tetrahydrozoline hydrochloride, xylometazoline
hydrochloride, and ethylnorepinephrine hydrochloride; (10)
anticholinergic agents such as ipratropium bromide, tiotropium
bromide, oxitropium bromide, aclindinium bromide, glycopyrrolate,
(R,R)-glycopyrrolate, pirenzepine, and telenzepine; (11)
.beta.-adrenoceptor agonists such as metaproterenol, isoproterenol,
isoprenaline, albuterol, formoterol (particularly the fumarate
salt), salmeterol (particularly the xinafoate salt), terbutaline,
orciprenaline, bitolterol mesylate, fenoterol, and pirbuterol, or
methylxanthanines including theophylline and aminophylline, sodium
cromoglycate; (12) insulin-like growth factor type I (IGF-1)
mimetic; (13) glucocortico steroids, especially inhaled
glucocorticoid with reduced systemic side effects, such as
prednisone, prednisolone, flunisolide, triamcinolone acetonide,
beclomethasone dipropionate, budesonide, fluticasone propionate,
ciclesonide and mometasone furoate; (14) kinase inhibitors such as
inhibitors of the Janus Kinases (JAK 1 and/or JAK2 and/or JAK 3
and/or TYK2) such as tofacitinib (Pfizer), baricitinib (Incyte),
VX-509 (Vertex), ASP-015K (Astellas), GLPG0634 (Galapagos), SB-1578
(SBIO), and AC-430 (Ambit Biosciences); p38 MAPK and IKK2; (15)
B-cell targeting biologics such as rituximab (Rituxan.RTM.); (16)
selective costimulation modulators such as abatacept (Orencia);
(17) interleukin inhibitors, such as IL-1 inhibitor anakinra
(Kineret) and IL-6 inhibitor tocilizumab (Actemra).
[0167] The present invention also provides for so-called "triple
combination" therapy, comprising a compound of formula I or a
pharmaceutically acceptable salt thereof together with
beta.sub.2-adrenoreceptor agonist and an anti-inflammatory
corticosteroid. Preferably this combination is for treatment and/or
prophylaxis of asthma, COPD or allergic rhinitis. The
beta.sub.2-adrenoreceptor agonist and/or the anti-inflammatory
corticosteroid can be as described above and/or as described in WO
03/030939 A1. Representative examples of such a "triple"
combination are a compound of formula I or a pharmaceutically
acceptable salt thereof in combination with the components of
Advair.RTM. (salmeterol xinafoate and fluticasone propionate),
Symbicort.RTM. (budesonide and formoterol fumarate), or Dulera.RTM.
(mometasone furoate and formoterol fumarate), salmeterol or a
pharmaceutically acceptable salt thereof (e.g., salmeterol
xinafoate) and fluticasone propionate.
[0168] For the treatment of cancer a compound of formula I may be
combined with one or more of an anticancer agent. Examples of such
agents can be found in Cancer Principles and Practice of Oncology
by V. T. Devita and S. Hellman (editors), 6.sup.th edition (Feb.
15, 2001), Lippincott Williams & Wilkins Publishers. A person
of ordinary skill in the art would be able to discern which
combinations of agents would be useful based on the particular
characteristics of the drugs and the cancer involved. Such
anti-cancer agents include, but are not limited to, the following:
(1) estrogen receptor modulator such as diethylstibestral,
tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene,
fluoxymestero, and SH646; (2) other hormonal agents including
aromatase inhibitors (e.g., aminoglutethimide, tetrazole
anastrozole, letrozole and exemestane), luteinizing hormone release
hormone (LHRH) analogues, ketoconazole, goserelin acetate,
leuprolide, megestrol acetate and mifepristone; (3) androgen
receptor modulator such as finasteride and other 5.alpha.-reductase
inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and
abiraterone acetate; (4) retinoid receptor modulator such as
bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,
.alpha.-difluoromethylornithine, ILX23-7553,
trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl
retinamide; (5) antiproliferative agent such as antisense RNA and
DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and
INX3001, and antimetabolites such as enocitabine, carmofur,
tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine,
capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium
hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin,
decitabine, nolatrexed, pemetrexed, nelzarabine,
2'-deoxy-2'-methylidenecytidine, fluoromethylene-2'-deoxycytidine,
N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L--
manno-heptopyranosyl]adenine, aplidine, ecteinascidin,
troxacitabine, aminopterin, 5-flurouracil, floxuridine,
methotrexate, leucovarin, hydroxyurea, thioguanine (6-TG),
mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine
phosphate, cladribine (2-CDA), asparaginase, gemcitabine,
alanosine, swainsonine, lometrexol, dexrazoxane, methioninase, and
3-aminopyridine-2-carboxaldehyde thiosemicarbazone; (6)
prenyl-protein transferase inhibitor including farnesyl-protein
transferase (FPTase), geranylgeranyl-protein transferase type I
(GGPTase-I), and geranylgeranyl-protein transferase type-II
(GGPTase-11, also called Rab GGPTase); (7) HMG-CoA reductase
inhibitor such as lovastatin, simvastatin, pravastatin,
atorvastatin, fluvastatin and rosuvastatin; (8) angiogenesis
inhibitor such as inhibitors of the tyrosine kinase receptors Flt-1
(VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived,
fibroblast-derived, or platelet derived growth factors, MMP (matrix
metalloprotease) inhibitors, integrin blockers, interferon-.alpha.,
interleukin-12, erythropoietin (epoietin-.alpha.), granulocyte-CSF
(filgrastin), granulocyte, macrophage-CSF (sargramostim), pentosan
polysulfate, cyclooxygenase inhibitors, steroidal
anti-inflammatories, carboxyamidotriazole, combretastatin A-4,
squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide,
angiostatin, troponin-1, angiotensin II antagonists, heparin,
carboxypeptidase U inhibitors, and antibodies to VEGF, endostatin,
ukrain, ranpirnase, IM862, acetyldinanaline,
5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triaz-
ole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610,
NX31838, sulfated mannopentaose phosphate, and
3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416); (9)
PPAR-.gamma. agonists, PPAR-.delta. agonists, thiazolidinediones
(such as DRF2725, CS-011, troglitazone, rosiglitazone, and
pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570,
SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344,
KRP297, NP0110, DRF4158, NN622, GI262570, PNU 182716, DRF552926,
2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpro-
pionic acid (disclosed in U.S. Ser. No. 09/782,856), and
(2R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-
-carboxylic acid (disclosed in U.S. Ser. No. 60/235,708 and
60/244,697); (9) inhibitor of inherent multidrug resistance
including inhibitors of p-glycoprotein (P-gp), such as LY335979,
XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar); (10)
inhibitor of cell proliferation and survival signaling such as
inhibitors of EGFR (for example gefitinib and erlotinib),
inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGF1R
such as MK-0646 (dalotuzumab), inhibitors of CD20 (rituximab),
inhibitors of cytokine receptors, inhibitors of MET, inhibitors of
PI3K family kinase (for example LY294002), serine/threonine kinases
(including but not limited to inhibitors of Akt such as described
in (WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO
02/083675, WO 02/083139, WO 02/083140 and WO 02/083138), inhibitors
of Raf kinase (for example BAY-43-9006), inhibitors of MEK (for
example CI-1040 and PD-098059) and inhibitors of mTOR (for example
Wyeth CCI-779 and Ariad AP23573); (11) a bisphosphonate such as
etidronate, pamidronate, alendronate, risedronate, zoledronate,
ibandronate, incadronate or cimadronate, clodronate, EB-1053,
minodronate, neridronate, piridronate and tiludronate; (12)
.gamma.-secretase inhibitors, (13) agents that interfere with
receptor tyrosine kinases (RTKs) including inhibitors of c-Kit,
Eph, PDGF, Flt3 and c-Met; (14) agent that interferes with a cell
cycle checkpoint including inhibitors of ATR, ATM, the Chk1 and
Chk2 kinases and cdk and cdc kinase inhibitors and are specifically
exemplified by 7-hydroxystaurosporin, flavopiridol, CYC202
(Cyclacel) and BMS-387032; (15) BTK inhibitors such as PCI32765,
AVL-292 and AVL-101; (16) PARP inhibitors including iniparib,
olaparib, AG014699, ABT888 and MK4827; (16) ERK inhibitors; (17)
mTOR inhibitors such as sirolimus, ridaforolimus, temsirolimus,
everolimus; (18) cytotoxic/cytostatic agents.
[0169] "Cytotoxic/cytostatic agents" refers to compounds which
cause cell death or inhibit cell proliferation primarily by
interfering directly with the cell's functioning or inhibit or
interfere with cell mytosis, including alkylating agents, tumor
necrosis factors, intercalators, hypoxia activatable compounds,
microtubule inhibitors/microtubule-stabilizing agents, inhibitors
of mitotic kinesins, inhibitors of histone deacetylase, inhibitors
of kinases involved in mitotic progression, antimetabolites;
biological response modifiers; hormonal/anti-hormonal therapeutic
agents, haematopoietic growth factors, monoclonal antibody targeted
therapeutic agents, topoisomerase inhibitors, proteasome inhibitors
and ubiquitin ligase inhibitors.
[0170] Examples of cytotoxic agents include, but are not limited
to, sertenef, cachectin, chlorambucil, cyclophosphamide,
ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa,
busulfan, carmustine, lomustine, streptozocin, tasonermin,
lonidamine, carboplatin, altretamine, dacarbazine, procarbazine,
prednimustine, dibromodulcitol, ranimustine, fotemustine,
nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine,
improsulfan tosilate, trofosfamide, nimustine, dibrospidium
chloride, pumitepa, lobaplatin, satraplatin, profiromycin,
cisplatin, irofulven, dexifosfamide,
cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine,
glufosfamide, GPX100, (trans, trans,
trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(c-
hloro)platinum (II)]tetrachloride, diarizidinylspermine, arsenic
trioxide,
1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine,
zorubicin, doxorubicin, daunorubicin, idarubicin, anthracenedione,
bleomycin, mitomycin C, dactinomycin, plicatomycin, bisantrene,
mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin,
antineoplaston,
3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin,
annamycin, galarubicin, elinafide, MEN10755, and
4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin.
[0171] An example of a hypoxia activatable compound is
tirapazamine.
[0172] Examples of proteasome inhibitors include but are not
limited to lactacystin and bortezomib.
[0173] Examples of microtubule inhibitors/microtubule-stabilising
agents include vincristine, vinblastine, vindesine, vinzolidine,
vinorelbine, vindesine sulfate,
3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, podophyllotoxins
(e.g., etoposide (VP-16) and teniposide (VM-26)), paclitaxel,
docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin,
cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin,
anhydrovinblastine,
N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butyla-
mide, TDX258, the epothilones (see for example U.S. Pat. Nos.
6,284,781 and 6,288,237) and BMS188797.
[0174] Some examples of topoisomerase inhibitors are topotecan,
hycaptamine, irinotecan, rubitecan,
6-ethoxypropionyl-3',4'-O-exo-benzylidene-chartreusin, lurtotecan,
7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100,
BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,
2'-dimethylamino-2'-deoxy-etoposide, GL331,
N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazo-
le-1-carboxamide, asulacrine,
2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridiniu-
m,
5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H--
pyrazolo[4,5,1-de]acridin-6-one,
N-[1-[2-(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmeth-
yl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,
6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-on-
e, and dimesna.
[0175] Examples of inhibitors of mitotic kinesins include, but are
not limited to inhibitors of KSP, inhibitors of MKLP1, inhibitors
of CENP-E, inhibitors of MCAK, inhibitors of Kif14, inhibitors of
Mphosph1 and inhibitors of Rab6-KIFL.
[0176] Examples of "histone deacetylase inhibitors" include, but
are not limited to, vorinostat, trichostatin A, oxamflatin, PXD101,
MG98, valproic acid and scriptaid.
[0177] "Inhibitors of kinases involved in mitotic progression"
include, but are not limited to, inhibitors of aurora kinase,
inhibitors of Polo-like kinases (PLK; in particular inhibitors of
PLK-1), inhibitors of bub-1 and inhibitors of bub-R1. An example of
an "aurora kinase inhibitor" is VX-680.
[0178] "Antiproliferative agents" includes antisense RNA and DNA
oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and
INX3001, and antimetabolites such as enocitabine, carmofur,
tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine,
capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium
hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin,
decitabine, nolatrexed, pemetrexed, nelzarabine,
2'-deoxy-2'-methylidenecytidine, fluoromethylene-2'-deoxycytidine,
N6-[4-deoxy-4-[N2-[2,4-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno--
heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine,
aminopterin, 5-flurouracil, floxuridine, methotrexate, leucovarin,
hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine,
pentostatin, fludarabine phosphate, cladribine (2-CDA),
asparaginase, gemcitabine, alanosine, swainsonine, lometrexol,
dexrazoxane, methioninase, and 3-aminopyridine-2-carboxaldehyde
thiosemicarbazone.
[0179] Non-limiting examples of suitable agents used in cancer
therapy that may be combined with compounds of formula I include,
but are not limited to, abarelix; aldesleukin; alemtuzumab;
alitretinoin; allopurinol; altretamine; amifostine; anastrozole;
arsenic trioxide; asparaginase; azacitidine; bendamustine;
bevacuzimab; bexarotene; bleomycin; bortezomib; busulfan;
calusterone; capecitabine; carboplatin; carmustine; cetuximab;
chlorambucil; cisplatin; cladribine; clofarabine; cyclophosphamide;
cytarabine; dacarbazine; dactinomycin, actinomycin D; dalteparin;
darbepoetin alfa; dasatinib; daunorubicin; degarelix; denileukin
diftitox; dexrazoxane; docetaxel; doxorubicin; dromostanolone
propionate; eculizumab; Elliott's B Solution; eltrombopag;
epirubicin; epoetin alfa; erlotinib; estramustine; etoposide
phosphate; etoposide; everolimus; exemestane; filgrastim;
floxuridine; fludarabine; fluorouracil; fulvestrant; gefitinib;
gemcitabine; gemtuzumab ozogamicin; goserelin acetate; histrelin
acetate; hydroxyurea; ibritumomab tiuxetan; idarubicin; ifosfamide;
imatinib mesylate; interferon alfa 2a; interferon alfa-2b;
irinotecan; ixabepilone; lapatinib; lenalidomide; letrozole;
leucovorin; leuprolide acetate; levamisole; lomustine;
meclorethamine, nitrogen mustard; megestrol acetate; melphalan,
L-PAM; mercaptopurine; mesna; methotrexate; methoxsalen; mitomycin
C; mitotane; mitoxantrone; nandrolone phenpropionate; nelarabine;
nilotinib; Nofetumomab; ofatumumab; oprelvekin; oxaliplatin;
paclitaxel; palifermin; pamidronat; panitumumab; pazopanib;
pegademase; pegaspargase; Pegfilgrastim; pemetrexed disodium;
pentostatin; pipobroman; plerixafor; plicamycin, mithramycin);
porfimer sodium; pralatrexate; procarbazine; quinacrine;
Rasburicase; raloxifene hydrochloride; Rituximab; romidepsin;
romiplostim; sargramostim; sargramostim; satraplatin; sorafenib;
streptozocin; sunitinib maleate; tamoxifen; temozolomide;
temsirolimus; teniposide; testolactone; thioguanine; thiotepa;
topotecan; toremifene; tositumomab; trastuzumab; tretinoin; uracil
mustard; valrubicin; vinblastine; vincristine; vinorelbine;
vorinostat; and zoledronate.
[0180] It will be clear to a person skilled in the art that, where
appropriate, the other therapeutic ingredient(s) may be used in the
form of salts, for example as alkali metal or amine salts or as
acid addition salts, or prodrugs, or as esters, for example lower
alkyl esters, or as solvates, for example hydrates, to optimise the
activity and/or stability and/or physical characteristics, such as
solubility, of the therapeutic ingredient. It will be clear also
that, where appropriate, the therapeutic ingredients may be used in
optically pure form.
[0181] The combinations referred to above may conveniently be
presented for use in the form of a pharmaceutical composition and
thus pharmaceutical compositions comprising a combination as
defined above together with a pharmaceutically acceptable diluent
or carrier represent a further aspect of the invention. These
combinations are of particular interest in respiratory diseases and
are conveniently adapted for inhaled or intranasal delivery.
[0182] The individual compounds of such combinations may be
administered either sequentially or simultaneously in separate or
combined pharmaceutical compositions. Preferably, the individual
compounds will be administered simultaneously in a combined
pharmaceutical composition. Appropriate doses of known therapeutic
agents will be readily appreciated by those skilled in the art.
[0183] Syk inhibition may be determined using the following assay
protocol:
Biological Assay
[0184] Homogeneous Time-Resolved Fluorescence (HTRF) Assay for the
Recombinant Human Syk Enzyme:
[0185] A recombinant GST-hSyk fusion protein was used to measure
potency of compounds to inhibit human Syk activity. The recombinant
human GST-Syk (Curia Biosciences #08-176) (5 pM final
concentration) was incubated with various concentrations of the
inhibitor diluted in DMSO (0.1% final concentration) for 10 minutes
at room temperature in 15 mM Tris-HCl (pH 7.5), 0.01% tween 20, 2
mM DTT in 384 well plate format. To initiate the reaction the
biotinylated substrate peptide (250 nM final concentration) that
contains the phosphorylation site for Syk was added with magnesium
(5 mM final concentration) and ATP (25 .mu.M final concentration).
Final volume of the reaction was 10 .mu.L. Phosphorylation of the
peptide was allowed to proceed for 45 minutes at room temperature.
To quench the reaction and detect the phosphorylated product, 2 nM
of a Europium-anti-phosphotyrosine antibody (Perkin Elmer #AD0161)
and 70 nM SA-APC (Perkin-Elmer #CR130-100) were added together in
15 mM Tris pH 7.5, 40 mM EDTA, 0.01% tween 20. Final volume of the
quenching solution was 10 .mu.L. The resulting HTRF signal was
measured after 30 minutes on an EnVision (Perkin-Elmer) reader
using a time-resolved fluorescence protocol. IC.sub.50 was
determined following 10-dose titration (10 .mu.M to 0.508 nM) and
four parameter logistic curve fitting using the Merck Assay Data
Analyzer. The rhSyk activity (IC.sub.50) is expressed as +++(100 nM
or less), ++(between 100 and 1000 nM), +(between 1 and 10 .mu.M).
IC.sub.50 values are also provided for the following representative
compounds:
TABLE-US-00006 Example No. rhSyk (nM) Example 1, Enantiomer 1 2.9
Example 2, racemic mixture 3.1 Example 9, Enantiomer 1 278 Example
10 0.1 Example 11 0.5 Example 14, Step 2 0.5 Example 14-2 219
Example 14-4 0.5 Example 14-14 0.5 Example 14-15 0.5 Example 14-28
1.1 Example 14-50 6
[0186] The compounds of this invention may be made by a variety of
methods, including standard chemistry. Any previously defined
variable will continue to have the previously defined meaning
unless otherwise indicated. Illustrative general synthetic methods
are set out below and then specific compounds of the invention are
prepared in the Examples.
[0187] Compounds of general formula I may be prepared by methods
known in the art of organic synthesis as set forth in part by the
following synthesis schemes. In all of the schemes described below,
it is well understood that protecting groups for sensitive or
reactive groups are employed where necessary in accordance with
general principles of chemistry. Protecting groups are manipulated
according to standard methods of organic synthesis (T. W. Green and
P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John
Wiley & Sons). These groups are removed at a convenient stage
of the compound synthesis using methods that are readily apparent
to those skilled in the art. The selection of protecting groups as
well as the reaction conditions and order of reaction steps shall
be consistent with the preparation of compounds of formula I. Those
skilled in the art will recognize if a stereocenter exists in
compounds of formula I. Accordingly, the present invention includes
all possible stereoisomers and includes not only mixtures of
stereoisomers (such as racemic compounds) but the individual
stereoisomers as well. When a compound is desired as a single
enantiomer, it may be obtained by stereospecific or stereoselective
synthesis or by resolution of the final product or any convenient
intermediate. Resolution of the final product, an intermediate, or
a starting material may be affected by any suitable method known in
the art. See, for example, Stereochemistry of Organic Compounds by
E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience,
1994).
[0188] The following abbreviations are used in the schemes and
examples: Ac=Acetyl; AcOH=Acetic acid; Bn=benzyl; Boc
(t-Boc)=4-butyloxycarbonyl;
BOP=(Benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium
hexafluorophosphate; DAST=(Diethylamino)sulfur trifluoride;
dba=dibenzylideneacetone; DCE=1,2-dichloroethane;
DCM=Dichloromethane; Dibal/Dibal-H=Diisobutylaluminum hydride;
DIPEA/DIEA=Diisopropylethylamine; DMAP=N,N-dimethyl-aminopyridine;
DME=1,2-dimethoxyethane; DMF=Dimethyl formamide;
DMSO=Dimethyl-sulfoxide; Dppf=1,1'-Bis(diphenylphosphino)ferrocene;
EDC=N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide; EtOAc=Ethyl
acetate;
HATU=N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate; HMDS=Hexamethyldisilazane;
HOBT=1-Hydroxybenzo-triazole; IPA=Isopropyl alcohol; LDA=Lithium
diisopropylamide; mCPBA=Meta-chloroperoxy-benzoic acid;
Ms=Methanesulfonyl (mesyl); MTBE=Methyl t-butyl ether;
NBS=N-bromo-succinimide; Ph phenyl; TBAF=t-butylammonium fluoride;
TBDMS/TBS=t-butyl dimethylsilyl; TFA=Trifluoroacetic
acid/trifluroacetate; THF=Tetrahydrofuran; TLC=Thin-layer
chromatography; TMS=Trimethylsilyl; Ts=Toluenesulfonyl (tosyl);
TSA=p-toluenesulfonic acid. Abbreviations for alkyl/cycloalkyl
groups: Me=methyl, Et=ethyl, nPr=n-propyl, iPr=isopropyl,
nBu=n-butyl, t-Bu=tertiary butyl, cPr=cyclopropyl, cBu=cyclobutyl,
cPen=cyclopentyl, cHex=cyclohexyl, cHept=cycloheptyl.
##STR00008##
[0189] Compounds of formula I may be prepared by palladium-mediated
coupling of substituted amino pyridines (1) with pyridyl thiazoles
(2). Alternatively, compounds of formula I can also be obtained by
reacting substituted aminobispyridines (3) with substituted
thiazoles (4).
##STR00009##
[0190] Compounds of formula (2) can be prepared by coupling a
bis-halo pyridine of type (5) with thiazole using a palladium
catalyst. The pyridyl thiazole (6) can be deprotonated with a
strong base, such as LDA, and reacted with an electrophile like (7)
to provide (2).
##STR00010##
[0191] As depicted in scheme 3, compounds of formula (2) can also
be prepared by first deprotonating thiazole with a strong base,
such as LDA, and reacting the resultant species with an
electrophile like (7) to yield substituted thiazole (8). Reaction
of the thiazole (8) with a bis-halo pyridine (5) affords compounds
of formula (2).
##STR00011##
[0192] Aminobispyridines (3) can be synthesized according to scheme
4. Coupling of aminopyridines (9) with bis-halo pyridines (10)
using a palladium catalyst provides compounds of formula (3).
##STR00012##
[0193] Some compounds of formula I are represented by carboxylic
esters (11). Preparation of carboxylic acids (12) and amides (13)
is demonstrated in Scheme 5. Carboxylic esters of type (11) can be
hydrolyzed under basic conditions to yield carboxylic acids (12),
which can be further derivatized using standard amide coupling
reagents and amines to afford amides of formula (13).
##STR00013##
[0194] As depicted in Scheme 6, compounds of formula (15) can be
prepared by reaction of amine (14) with electrophiles, such as
potassium cyanate.
[0195] Compounds of formula I can be prepared according to the
procedures described in the Schemes and Examples herein, using
appropriate materials and are further exemplified by the following
specific examples. The compounds exemplified are illustrative of
the invention and are not, however, to be construed as limiting the
scope of the invention in any manner. The examples further
illustrate details for the preparation of the compounds of the
present invention. Those skilled in the art will readily understand
that known variations of protecting groups, of reagents, as well as
of the conditions and processes of the following preparative
procedures, can be used to prepare these compounds. It is also
understood that whenever a chemical reagent is not commercially
available, such a chemical reagent can be readily prepared by those
skilled in the art by either following or adapting known methods
described in the literature. All temperatures are degrees Celsius
unless otherwise noted. Mass spectra (MS) were measured either by
electrospray ion-mass spectroscopy (ESI) or by atmospheric pressure
chemical ionization mass spectroscopy (APCI).
Intermediate 1. Butyl trans-4-acetylcyclohexanecarboxylate
##STR00014##
[0197] To a vented and cooled solution (0.degree. C.) under
nitrogen of trans-4-(butoxycarbonyl)cyclohexanecarboxylic acid (J.
Chem. Soc., Perkin Trans. 1, 1999, 20, 3023) (18.9 g, 83 mmol) in
CH.sub.2Cl.sub.2 (150 mL) was added a catalytic amount of DMF (30
.mu.L) followed by oxalyl chloride (7.97 mL, 91 mmol). The reaction
mixture was then allowed to slowly warm to room temperature where
it was stirred for 14 h at which point it was concentrated to a
yellow oil and dried under vacuum for 3 h. The residue consisting
primarily of butyl trans-4-(chlorocarbonyl)cyclohexanecarboxylate
was diluted with THF (200 mL) and cooled in an ice bath. To this
solution was added PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (3.38 g, 4.14
mmol) followed by dimethyl zinc (2 M in PhCH.sub.3, 29 mL, 58 mmol)
at such a rate that the internal temperature did not exceed
15.degree. C. The cooling bath was then removed and after 2 h of
stirring at room temperature the reaction mixture was re-cooled to
0.degree. C. where it was diluted carefully with H.sub.2O. After
the initial exotherm had subsided, sufficient 1N HCl and EtOAc were
introduced such that a homogenous biphasic mixture formed. The
layers were separated, the organic washed a second time with
H.sub.2O then dried with MgSO.sub.4, filtered and concentrated in
vacuo. The crude residue was absorbed on silica and purified by
flash chromatography to afford butyl
trans-4-acetylcyclohexanecarboxylate as a non-viscous orange oil.
MS ESI calc'd. for C.sub.13H.sub.23O.sub.3 [M+H].sup.+ 227. found
227. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 4.06 (t, J=6.6 Hz,
2H), 2.37-2.29 (m, 1H), 2.28-2.20 (m, 1H), 2.14 (s, 3H), 2.11-2.02
(m, 2H), 1.99 (d, J=13.8 Hz, 2H), 1.66-1.55 (m, 2H), 1.51-1.40 (m,
2H), 1.39-1.29 (m, 4H), 0.93 (t, J=7.4 Hz, 3H).
Intermediate 2. Butyl
trans-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate
and butyl
trans-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexaneca-
rboxylate
##STR00015##
[0199] To a cooled (0.degree. C.) flask under nitrogen containing
iPrMgCl--LiCl (1.3 M in THF, 55.2 mL, 71.8 mmol) was added thiazole
(5.10 mL, 71.8 mmol) keeping the internal temperature<10.degree.
C. The resulting heterogenous mixture was warmed to RT where it was
stirred for 10 min then re-cooled to -20.degree. C. Then, a
solution of butyl trans-4-acetylcyclohexanecarboxylate (12.5 g,
55.2 mmol) in THF (20+5 mL) was added via syringe. The cooling bath
was then removed and the reaction mixture warmed slowly to
10.degree. C. during which time it was observed to nearly
completely homogenize. After 40 min, saturated aqueous NH.sub.4Cl
followed by EtOAc were added and the layers separated, the organics
dried over MgSO.sub.4, filtered and concentrated in vacuo. The
crude residue was absorbed on silica and purified by flash
chromatography to afford butyl
trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate
as a light yellow oil. The enantiomers were separated by chiral SFC
(Chiral Technology AZ-H, 2.1.times.25 cm, 5 uM, 45/55
MeOH/CO.sub.2, Flow Rate: 80 mL/min, 6 min run time, WL: 220 nm)
Elution was observed at 2.98 min and 4.14 min. Pooled fractions of
each peak were separately concentrated under reduced pressure.
[0200] Peak 1 (retention time=2.98 min): MS ESI calc'd. for
C.sub.16H.sub.25NO.sub.3S [M+H].sup.+ 312. found 312. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.67 (d, J=2.9, 1H), 7.51 (d,
J=2.9, 1H), 5.73 (s, 1H), 3.95 (t, J=6.5, 2H), 2.16-2.01 (m, 1H),
1.95-1.74 (m, 3H), 1.62 (t, J=11.1, 1H), 1.54-1.34 (m, 6H),
1.34-1.08 (m, 5H), 1.06-0.91 (m, 1H), 0.85 (t, J=7.3, 3H).
[0201] Peak 2 (retention time=4.14 min) MS ESI calc'd. for
C.sub.16H.sub.25NO.sub.3S [M+H].sup.+ 312. found 312. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.67 (d, J=2.9, 1H), 7.51 (d,
J=2.9, 1H), 5.73 (s, 1H), 3.95 (t, J=6.5, 2H), 2.16-2.01 (m, 1H),
1.95-1.74 (m, 3H), 1.62 (t, J=11.1, 1H), 1.54-1.34 (m, 6H),
1.34-1.08 (m, 5H), 1.06-0.91 (m, 1H), 0.85 (t, J=7.3, 3H).
Intermediate 3.
6-Bromo-N-(4-cyclopropylpyridin-2-yl)-4-methylpyridin-2-amine
##STR00016##
[0203] A dry round bottomed flask was charged with
2-amino-4-cyclopropylpyridine (5.00 g, 31.7 mmol) and
2,6-dibromo-4-methylpyridine (7.95 g, 31.7 mmol). The reaction
vessel was placed under an atmosphere of nitrogen (3.times.
vacuum/N2 cycle), then 1,4-dioxane (100 mL) was added and the
mixture was degassed with a steady stream of nitrogen for 30
minutes. Sodium tert-butoxide (3.35 g, 34.8 mmol) and
1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride
(0.49 g, 0.75 mmol) were added to the reaction flask, then the
reaction was stirred at room temperature for 15 minutes then heated
to 50.degree. C. for five hours. After cooling to room temperature
for 14 hours, the resulting reaction mixture was poured into water
(200 mL) and extracted with ethyl acetate (2.times.100 mL). The
combined organic layers were further washed with water and brine
(200 mL portions). The organic phase was dried over sodium sulfate,
filtered, and concentrated under reduced pressure to yield an oil.
The crude product was purified by silica gel chromatography (0-30%
ethyl acetate/hexanes) to give the title compound as a brown solid.
.sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 9.80 (s, 1H), 8.06 (d,
J=5.3 Hz, 1H), 7.70 (s, 1H), 7.23 (s, 1H), 6.92 (s, 1H), 6.61 (dd,
J=1.4, 5.3 Hz, 1H), 2.25 (s, 3H), 1.91-1.78 (m, 1H), 1.09-0.98 (m,
2H), 0.82-0.66 (m, 2H).
Intermediate 4. Butyl
trans-4-{1(R)-[5-(6-bromopyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}c-
yclohexanecarboxylate and butyl
trans-4-{1(S)-[5-(6-bromopyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}c-
yclohexanecarboxylate
##STR00017##
[0205] Step 1:
[0206] A suspension of 2,6-dibromopyridine (11.13 g, 47.0 mmol),
pivalic acid (0.545 mL, 4.70 mmol), potassium carbonate (6.49 g,
47.0 mmol) in N,N-dimethylacetamide (45 mL) was deoxygenated by
bubbling argon through it for 20 minutes. Thiazole (1.681 mL, 23.49
mmol) and tetrakis(triphenylphosphine)palladium(0) (1.086 g, 0.940
mmol) were added, the flask was sealed, and the reaction mixture
was heated to 115.degree. C. for 18 hours. The reaction mixture was
cooled to room temperature and then diluted with water (50 mL),
ethyl acetate (50 mL), and diethyl ether (50 mL). The layers were
separated and then the organic layer was washed with water
(2.times.50 mL), saturated aqueous sodium bicarbonate solution (25
mL), and brine (50 mL) The organic layer was dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel (10-60% ethyl
acetate/hexanes) to provide 2-bromo-6-(1,3-thiazol-5-yl)pyridine.
MS ESI calc'd. for C.sub.8H.sub.5BrN.sub.2S [M+H].sup.+ 241 and
243. found 241 and 243. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
9.19 (s, 1H), 8.64 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.83 (t, J=7.8
Hz, 1H), 7.58 (d, J=7.8 Hz, 1H).
[0207] Step 2:
[0208] To a solution of 2-bromo-6-(1,3-thiazol-5-yl)pyridine (457
mg, 1.895 mmol) in tetrahydrofuran (20 mL) at -78.degree. C. was
added lithium diisopropyl amide (1.8 M in
tetrahydrofuran/heptane/ethylbenzene, 1.106 mmol, 1.990 mmol) over
three minutes. After 30 minutes, a solution of butyl
trans-4-acetylcyclohexanecarboxylate (450 mg, 1.990 mmol) in
tetrahydrofuran (3 mL) was added to the reaction mixture. After an
additional 70 minutes, a saturated aqueous ammonium chloride
solution (10 mL) was added. Then, the reaction mixture was allowed
to warm to room temperature before being diluted with ethyl acetate
(50 mL), water (2 mL), and saturated aqueous ammonium chloride
solution (10 mL). The layers were separated and the organic layer
was sequentially washed with saturated aqueous sodium bicarbonate
solution and brine, dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (0-20% ethyl acetate/dichloromethane)
to give butyl
trans-4-{1-[5-(6-bromopyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}cycl-
ohexanecarboxylate. MS ESI calc'd. for
C.sub.21H.sub.27BrN.sub.2O.sub.3S [M+H].sup.+ 467 and 469. found
467 and 469. Two enantiomers were separated by chiral super
critical fluid chromatography (Chiral Technology IC-H, 2.1.times.25
cm, 5 uM, 70/30 ethanol/CO.sub.2, Flow Rate: 70 mL/min, 6 min run
time, WL: 220 nm) Elution was observed at 3.98 min and 4.76 min.
Pooled fractions of each peak were concentrated under reduced
pressure.
[0209] Enantiomer 1 (retention time=3.98 min): .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.12 (s, 1H), 7.61-7.51 (m, 2H), 7.37 (dd,
J=2.7, 5.9 Hz, 1H), 4.04 (t, J=6.6 Hz, 2H), 3.00 (s, 1H), 2.22-2.16
(m, 1H), 2.08-2.01 (m, 1H), 1.99 (d, J=13.4 Hz, 2H), 1.83-1.76 (m,
1H), 1.62-1.56 (m, 3H), 1.61 (s, 3H), 144-1.34 (m, 4H), 1.32-1.24
(m, 1H), 1.22-1.15 (m, 1H), 0.92 (t, J=7.4 Hz, 3H). Enantiomer 2
(retention time=4.76 min): .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.12 (s, 1H), 7.61-7.51 (m, 2H), 7.37 (dd, J=2.7, 5.9 Hz,
1H), 4.04 (t, J=6.6, 2H), 2.99 (s, 1H), 2.25-2.17 (m, 1H),
2.08-2.02 (m, 1H), 1.99 (d, J=12.8 Hz, 2H), 1.82-1.75 (m, 1H), 1.63
(s, 3H), 1.62-1.56 (m, 3H), 1.43 (m, 1H), 1.40-1.24 (m, 3H),
1.30-1.24 (m, 1H), 1.21-1.15 (m, 1H), 0.92 (t, J=7.4 Hz, 3H).
Intermediate 5.
6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2-amine
##STR00018##
[0211] Sodium tert-butoxide (5.87 g, 61.1 mmol) and
1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride
(0.905 g, 1.4 mmol) were added to a solution of
2,6-dibromo-4-methyl pyridine (13.9 g, 55.5 mmol) and
2-amino-4-trifluoromethyl pyridine (9.0 g, 55.5 mmol) in nitrogen
sparged dioxane (180 mL). The slurry was evacuated and refilled
with nitrogen. The mixture was stirred at 25.degree. C. for 15
minutes and then heated to 75.degree. C. for 12 hours. The reaction
mixture was cooled to 25.degree. C., water (20 mL) was added, and
the mixture was extracted with ethyl acetate (2.times.200 mL). The
combined extracts were dried over sodium sulfate, filtered,
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel to afford
6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2-amine
as a white solid. MS ESI calc'd. for
C.sub.12H.sub.10BrF.sub.3N.sub.3[M+H].sup.+ 332 and 334. found 332
and 334. .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 10.40 (s, 1H),
8.46 (d, J=6.0 Hz, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.18 (d, J=6.0
Hz, 1H), 7.00 (s, 1H), 2.25 (s, 3H).
[0212] The intermediates in the following table were prepared
according to the method described for Intermediate 5.
TABLE-US-00007 Exact Mass [M + H]+ Interm. Structure IUPAC Name [M
+ H]+ Observed 5.2 ##STR00019## 6-bromo-4-methyl-N-
(4-methylpyridin-2- yl)pyridin-2-amine 278 278, 280 5.3
##STR00020## 6-bromo-N-(4- cyclopropylpyridin-2-
yl)-4-methylpyridin-2- amine 304 304, 306 5.4 ##STR00021##
6-bromo-N-(4- methoxypyridin-2-yl) 4-methylpyridin-2- amine 294
294, 296 5.5 ##STR00022## N-(6-bromopyridin-2- yl)-4-
(trifluoromethyl)pyridin- 2-amine 318 318, 320 5.6 ##STR00023##
N-(6-bromopyridin-2- yl)-4-methylpyridin-2- amine 264 264, 266 5.7
##STR00024## N-(6-bromopyridin-2- yl)-4-methoxypyridin- 2-amine 280
280, 282 5.8 ##STR00025## N-(6-bromo-4- methylpyridin-2-yl)-5-
chloro-4- methylpyridin-2-amine 312 312, 314 5.9 ##STR00026##
4,6-dichloro-N-[4- (trifluoromethyl)pyridin- 2-yl]pyridin-2-amine
308 308 5.10 ##STR00027## 6-chloro-4- (difluoromethyl)-N-[4-
(trifluoromethyl)pyridin- 2-yl]pyridin-2-amine 324 324
Intermediate 6. 2,6-Dichloro-4-cyclopropylpyridine
##STR00028##
[0214] Cyclopropylzinc bromide (0.5 M in tetrahydrofuran, 15 mL,
7.3 mmol) was added to a mixture of 2,6-dichloro-4-iodopyridine
(1.0 g, 3.65 mmol) and tetrakis(triphenylphosphine)palladium(0)
(211 mg, 0.182 mmol) in anhydrous tetrahydrofuran (10 mL) at
0.degree. C. After being stirred at room temperature for 4 hours,
the reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (petroleum ether: ethyl
acetate=100:1) to provide 2,6-dichloro-4-cyclopropylpyridine. MS
ESI calc'd. for C.sub.8H.sub.8Cl.sub.2N [M+H].sup.+ 188. found 188.
.sup.1H NMR: (400 MHz, CDCl.sub.3) .delta. 6.89 (s, 2H), 1.87-1.80
(m, 1H), 1.18-1.13 (m, 2H), 0.84-0.80 (m, 2H).
Intermediate 7.
6-Bromo-N-[4-(difluoromethyl)pyridin-2-yl]-4-methylpyridin-2-amine
##STR00029##
[0216] Potassium t-butoxide (1.0 M in THF, 198 mL, 198 mmol) was
added to a solution of 6-bromo-4-methyl pyridine-2-amine (37 g, 198
mmol) and 2-chloro-4-(difluoromethyl)pyridine (42.1 g, 257 mmol) in
THF (60 mL) at 0.degree. C. The resulting mixture was heated to
reflux for 30 minutes then cooled to 0.degree. C., and a second
portion of potassium t-butoxide (1.0 M in THF, 80 mL, 80 mmol) was
added. The mixture was again heated to reflux for 30 minutes,
cooled to 0.degree. C., and a third portion of potassium t-butoxide
(1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again
heated to reflux for 30 minutes. After cooling to 0.degree. C., a
fourth portion of potassium t-butoxide (1.0 M in THF, 20 mL, 20
mmol) was added. Upon refluxing for 30 minutes, the reaction was
allowed to cool to room temperature, then diluted with saturated
aqueous NH.sub.4Cl (500 mL) and diluted with DCM (500 mL). The
layers were separated, and the aqueous layer was extracted a second
time with DCM (500 mL). The combined organic layers were dried with
Na.sub.2SO.sub.4, filtered through a pad of CELITE (150 g), and
concentrated in vacuo. The residue was triturated with DCM (100
mL), filtered, and washed with hexanes (2.times.50 mL) to afford
one portion of
6-bromo-N-[4-(difluoromethyl)pyridin-2-yl]-4-methylpyridin-2-amine.
The filtrate was concentrated, absorbed on silica gel and purified
via silica gel column chromatography (EtOAc/Hex) to afford a second
portion of
6-bromo-N-[4-(difluoromethyl)pyridin-2-yl]-4-methylpyridin-2-amine.
MS ESI calc'd. for C.sub.12H.sub.11BrF.sub.2N.sub.3 [M+H].sup.+ 314
and 316. found 314 and 316. .sup.1H NMR (600 MHz, DMSO-d.sub.6)
.delta. 10.20 (s, 1H), 8.35 (d, f=5.1 Hz, 1H), 7.69 (s, 1H), 7.64
(s, 1H), 7.01 (d, J=5.1 Hz, 1H), 6.96 (t, J=22.3 Hz, 1H), 6.95 (s,
1H), 2.24 (s, 3H).
[0217] The intermediates in the following table were prepared
according to the method described for Intermediate 7.
TABLE-US-00008 Exact Mass [M + H]+ Interm. Structure IUPAC Name [M
+ H]+ Observed 7.2 ##STR00030## N-(6-bromopyridin-2- yl)-4-
(difluoromethyl)pyridin- 2-amine 300 300, 302 7.3 ##STR00031##
N-(6-bromopyridin-2- yl)-4-(propan-2- yl)pyridin-2-amine 292 292,
294 7.4 ##STR00032## 6-bromo-4-methyl-N- [4-(propan-2-
yl)pyridin-2-yl]pyridin- 2-amine 306 306, 308 7.5 ##STR00033##
6-chloro-4-cyclopropyl- N-[4- (trifluoromethyl)pyridin-
2-yl]pyridin-2-amine 314 314
Intermediate 8. Methyl
trans-4-[cyclopropyl(hydroxy)1,3-thiazol-2-ylmethyl]cyclohexanecarboxylat-
e
##STR00034##
[0219] Step 1:
[0220] To a solution of
trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (500 mg, 2.69
mmol) in dichloromethane (3 mL) at 0.degree. C. was added oxalyl
chloride (0.26 mL, 2.95 mmol) dropwise. The solution was stirred at
0.degree. C. for 30 min and then allowed to warm to room
temperature and stirred for one hour. The solution was then cooled
back to 0.degree. C. and 2-(trimethylsilyl)-1,3-thiazole (0.63 mL,
4.03 mmol) was added. The solution was allowed to warm to room
temperature and then stirred for one hour. The solution was then
poured into cold saturated sodium bicarbonate and then diluted with
dichlormethane. The organic phase was separated, dried over
magnesium sulfate, filtered and concentrated in vacuo. The crude
product was purified by silica gel chromatography (0-30% ethyl
acetate/hexanes) to provide methyl
trans-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate. MS ESI
calc'd. for C.sub.12H.sub.16NO.sub.3S [M+H].sup.+ 254. found 254.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.01 (dd, J=1.6, 2.9 Hz,
1H), 7.67 (dd, J=1.7, 2.9 Hz, 1H), 3.77-3.67 (m, 3H), 3.62 (t,
J=11.1 Hz, 1H), 2.35 (t, J=10.4 Hz, 1H), 2.18-2.06 (m, 4H),
1.68-1.48 (m, 4H).
[0221] Step 2:
[0222] To a solution of methyl
trans-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate (2.59 g,
10.22 mmol) in THF (10 mL) at -78.degree. C. was added
cyclopropylmagnesium bromide (0.5 M in THF, 24 mL, 12.00 mmol) and
the solution was stirred at this temperature for three hours. The
solution was then allowed to warm for 15 minutes and then quenched
with aqueous ammonium chloride. The solution was diluted with
dichloromethane and the organic layer was separated, dried over
magnesium sulfate, filtered and concentrated in vacuo. The crude
product was purified by silica gel chromatography (0-30% ethyl
acetate/hexanes. The product was further purified by reverse phase
chromatography (25-100% acetonitrile/water with 0.1% TFA modifier)
to afford methyl
trans-4-[cyclopropyl(hydroxy)1,3-thiazol-2-ylmethyl]cyclohexanecarboxylat-
e. MS ESI calc'd. for C.sub.15H.sub.22NO.sub.3S [M+H].sup.+ 296.
found 296. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.77 (d, J=3.4
Hz, 1H), 7.37 (d, J=3.4 Hz, 1H), 3.65 (s, 3H), 2.28-2.17 (m, 1H),
2.13-2.02 (m, 3H), 2.01-1.90 (m, 2H), 1.56-1.48 (m, 1H), 1.48-1.39
(m, 1H), 1.39-1.32 (m, 1H), 1.33-1.19 (m, 3H), 0.75-0.62 (m, 1H),
0.61-0.50 (m, 1H), 0.42-0.25 (m, 2H).
Intermediate 9. methyl
trans-4-[2,2,2-trifluoro-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanec-
arboxylate
##STR00035##
[0224] To the solution of methyl
trans-4-(thiazole-2-carbonyl)cyclohexanecarboxylate (1.1 g, 4.34
mmol) in THF (20 mL) at 0.degree. C. was added
trifluoromethyltrimethylsilane (1.286 mL, 8.68 mmol).
Tetrabutylammonium fluoride trihydrate (1M in THF, 17.37 mL, 17.37
mmol) was added slowly maintaining the temperature at 0.degree. C.
The reaction was allowed to stir for 1 hr and then water (30 mL)
and ethyl acetate (30 mL) was added to quench the reaction. The
organic layer was removed, washed with brine (20 mL), dried over
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by chromatography on silica gel (0-20%
ethyl acetate in hexane) to afford methyl
trans-4-[2,2,2-trifluoro-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanec-
arboxylate. MS ESI calcd. for C.sub.13H.sub.17F.sub.3NO.sub.3S
[M+H].sup.+ 324. found 324. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.79 (d, J=3.2 Hz, 1H), 7.49 (d, J=3.2 Hz, 1H), 4.77 (s,
1H), 3.65 (s, 3H), 2.40 (m, 1H), 2.30-1.90 (m, 3H), 1.50-1.20 (m,
6H).
Intermediate 10 Methyl
trans-4-[hydroxy(1,3-thiazol-2-yl)methyl]cyclohexanecarboxylate
##STR00036##
[0226] To a solution of methyl
trans-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate (500 mg,
1.97 mmol) in methanol (20 mL) was added sodium borohydride (224
mg, 5.92 mmol) and the solution was stirred for one hour. The
solution was then diluted with ethyl acetate and water. The organic
layer was separated, dried over magnesium sulfate, filtered and
concentrated in vacuo. The crude product was purified by silica gel
chromatography to afford methyl
trans-4-[hydroxy(1,3-thiazol-2-yl)methyl]cyclohexanecarboxylate. MS
ESI calc'd. for C.sub.12H.sub.18NO.sub.3S [M+H].sup.+ 256. found
256. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.70 (d, J=3.2 Hz,
1H), 7.58 (d, J=3.2 Hz, 1H), 6.10 (d, J=5.2 Hz, 1H), 4.59 (t, J=5.1
Hz, 1H), 3.54 (s, 3H), 2.21-2.11 (m, 1H), 1.92-1.83 (m, 2H),
1.75-1.64 (m, 1H), 1.64-1.53 (m, 2H), 1.33-1.11 (m, 4H).
Intermediate 11. (1S,3R)-methyl
3-(thiazole-2-carbonyl)cyclopentanecarboxylate
(1S,3R)-methyl 3-(thiazole-2-carbonyl)cyclopentanecarboxylate
##STR00037##
[0228] To a solution of
(1R,3S)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (130 mg,
0.76 mmol) in dichloromethane (3 mL) was added DMF (5.85 .mu.L,
0.08 mmol). The solution was cooled to 0.degree. C. oxalyl chloride
(73.0 .mu.L, 0.83 mmol) was added. The mixture was stirred at
0.degree. C. for 30 minutes and then allowed to warm to room
temperature for one hour. The reaction was re-cooled to 0.degree.
C., 2-(trimethylsilyl)thiazole (178.0 mL, 1.13 mmol) was added and
the mixture was stirred at room temperature for two hours. The
mixture was diluted with dichloromethane and washed with saturated
sodium bicarbonate. The organic layer was separated, dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue
was purified by column chromatography on silica gel to afford
(1S,3R)-methyl 3-(thiazole-2-carbonyl)cyclopentanecarboxylate. MS
ESI calc'd. for C.sub.11H.sub.14NO.sub.3S [M+H].sup.+ 240. found
240. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.21 (d, J=3.0 Hz,
1H), 8.14 (d, J=3.0 Hz, 1H), 3.58 (s, 3H), 2.96-2.89 (m, 1H),
2.27-2.20 (m, 1H), 1.74-2.04 (m, 6H)
Intermediate 12. (1S,3R)-methyl
3-(1-hydroxy-1-(thiazol-2-yl)ethyl)cyclopentanecarboxylate
##STR00038##
[0230] To a solution of (1S,3R)-methyl
3-(thiazole-2-carbonyl)cyclopentanecarboxylate (148 mg, 1.75 mmol)
in THF (6 mL) and at -78.degree. C. was added methylmagnesium
bromide (582 mL, 1.75 mmol), the solution was stirred at
-78.degree. C. for 30 minutes. Saturated aqueous ammonium chloride
was added and the mixture was allowed to warm to room temperature.
The mixture was extracted with EtOAc, organic layer was dried over
magnesium sulfate, filtered and concentrated in vacuo. The crude
residue was absorbed on silica and purified by flash chromatography
to afford (1S,3R)-methyl
3-(1-hydroxy-1-(thiazol-2-yl)ethyl)cyclopentanecarboxylate. MS ESI
calc'd. for C.sub.12H.sub.18NO.sub.3S [M+H].sup.+ 256. found 256.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.67 (t, J=3.0 Hz, 1H),
7.50 (d, J=3.0 Hz, 1H), 3.58-3.57 (m, 3H), 3.52 (s, 1H), 2.75-2.62
(m, 1H), 2.43-2.35 (m, 1H), 1.97-1.91 (m, 1H), 1.78-1.51 (m, 4H),
1.46-1.44 (m, 3H), 1.25-1.19 (m, 1H).
Intermediate 13. Methyl
(1S,4S)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohex-
anecarboxylate
[0231] Methyl
(1S,4S)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohex-
anecarboxylate [0232] Methyl
(1S,4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohex-
anecarboxylate [0233] Methyl
(1S,4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohex-
anecarboxylate
##STR00039##
[0234] Step 1:
[0235] To a suspension of (methoxymethyl)triphenylphosphonium
chloride (38 g, 111 mmol) in THF (300 mL) at 0.degree. C. was added
potassium tert-butoxide (1.0 M in THF, 111 mL, 111 mmol) at such a
rate that the internal temperature did not exceed 7.degree. C.
After stirring for 1 hour at 0.degree. C., a solution of methyl
(1S)-2,2-dimethyl-4-oxocyclohexanecarboxylate (17 g, 92 mmol) in
THF (100 mL) was added via canula at such a rate that the internal
temperature did not exceed 7.degree. C. Upon completion the mixture
was slowly warmed to room temperature and stirred for 14 hours. The
reaction mixture was then cooled to 10.degree. C. and diluted with
water (100 mL) followed by 6 M HCl (250 mL). The resulting mixture
was stirred for 3 hours and then additional water (400 mL) and
EtOAc (500 mL) were added. The organic layer was separated and the
aqueous layer extracted a second time with EtOAc (500 mL). The
combined organic layers were dried over MgSO.sub.4, filtered,
absorbed on silica gel, and purified by silica gel chromatography
to afford a mixture of methyl
(1R,4R)-4-formyl-2,2-dimethylcyclohexanecarboxylate and methyl
(1R,4S)-4-formyl-2,2-dimethylcyclohexanecarboxylate. The product
was used immediately in the subsequent step. To a cooled
(-5.degree. C.) solution of iPrMgCl--LiCl (1.3 M in THF, 64 mL, 83
mmol) was added thiazole (6.27 mL, 88 mmol) at such a rate that the
internal temperature did not exceed 5.degree. C. After the addition
was complete, the resulting slurry was warmed to 15.degree. C. over
a period of 15 minutes, and then cooled to -10.degree. C. To this
slurry was added the mixture of
(1R,4R)-4-formyl-2,2-dimethylcyclohexanecarboxylate and methyl
(1R,4S)-4-formyl-2,2-dimethylcyclohexanecarboxylate (13.8 g, 69.6
mmol) as a solution in THF (30 mL) at such a rate the internal
temperature did not exceed 5.degree. C. The reaction mixture was
stirred for 30 minutes at 0.degree. C. and then quenched with water
(50 mL). EtOAc (500 mL) and 1N HCl (300 mL) were added. The organic
layer was separated, and the aqueous layer was extracted with EtOAc
(500 mL). The organic layers were combined, dried over MgSO.sub.4,
filtered, absorbed on silica gel, and purified by silica gel
chromatography to afford a diastereomeric mixture which was used
immediately in the subsequent step.
[0236] To the above mixture of secondary alcohols (16.3 g, 575
mmol) in dichloromethane (150 mL) at 10.degree. C. was added
Dess-Martin periodinane (25.4 g, 60 mmol). Upon warming to room
temperature, the temperature was controlled such that the internal
temperature did not exceed 35.degree. C. After 1 hour, the reaction
mixture was cooled to room temperature and sequentially diluted
with saturated aqueous NaHCO.sub.3 solution (300 mL), aqueous 5%
sodium sulfite solution (200 mL), and additional dichloromethane
(350 mL). The heterogeneous mixture was stirred until both layers
were clear, and then the layers were separated, and the aqueous
layer was extracted a second time with dichloromethane (500 mL).
The organic layers were combined, dried over MgSO.sub.4, filtered,
absorbed on silica, and purified by silica gel chromatography to
afford a mixture of methyl
(1S,4S)-2,2-dimethyl-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate
and methyl
(1S,4R)-2,2-dimethyl-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate.
The mixture was further purified by SFC to afford the above
compounds as single stereoisomers.
[0237] Characterization data for
(1S,4S)-2,2-dimethyl-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate:
MS ESI calc'd. for C.sub.14H.sub.20NO.sub.3S [M+H].sup.+ 282. found
282. .sup.1H NMR (600 MHz, CD.sub.3OD) .delta. 8.04 (d, J 3.1 Hz,
1H), 7.93 (d, J=3.0 Hz, 1H), 3.85 (tt, J=12.5, 3.4 Hz, 1H), 3.64
(s, 3H), 2.24 (dd, J=12.8, 3.6 Hz, 1H), 2.00 (ddd, J=12.7, 5.6, 3.1
Hz, 1H), 1.88 (ddd, J=26.6, 13.6, 3.9 Hz, 1H), 1.75 (ddd, J=13.9,
7.0, 3.7 Hz, 1H), 1.69 (ddd, J=13.2, 3.1, 2.1 Hz, 1H), 1.46-1.35
(m, 2H), 1.05 (s, 3H), 1.01 (s, 3H).
[0238] Characterization data for
(1S,4R)-2,2-dimethyl-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate:
MS ESI calc'd. for C.sub.14H.sub.20NO.sub.3S [M+H].sup.+ 282. found
282. .sup.1H NMR (600 MHz, CD.sub.3OD) .delta. 8.02 (d, J=3.1 Hz,
1H), 7.91 (d, J=3.1 Hz, 1H), 3.81 (tt, J=11.9, 3.8 Hz, 1H), 3.61
(s, 3H), 2.35 (d, J=3.8 Hz, 1H), 2.03 (t, J=12.6 Hz, 1H), 1.99-1.88
(m, 2H), 1.84-1.70 (m, 2H), 1.51-1.45 (m, 1H), 1.10 (s, 3H), 0.91
(s, 3H).
[0239] Step 2:
[0240] To a cooled (-40.degree. C.) solution of
(1S,4R)-2,2-dimethyl-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate
(2.3 g, 8.2 mmol) in THF (20 mL) was added MeMgBr (3.0 M in THF,
3.3 mL, 9.8 mmol) at such a rate that the internal temperature did
not increase above -30.degree. C. The mixture was then stirred for
15 minutes at -40.degree. C., quenched with saturated aqueous
ammonium chloride (40 mL), and warmed to room temperature. EtOAc
(20 mL) was added, the layers were separated, and the aqueous layer
was extracted a second time with EtOAc (30 mL). The organic layers
were combined, dried over MgSO.sub.4, filtered, absorbed on silica,
and purified by silica gel chromatography to afford a mixture of
methyl
(1S,4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohex-
anecarboxylate and methyl
(1S,4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohex-
anecarboxylate. Further purification was performed by SFC to afford
the single diastereomers. MS ESI calc'd. for
C.sub.i5H.sub.24NO.sub.3S [M+H].sup.+ 298. found 298.
[0241] Step 3:
[0242] To a cooled (-40.degree. C.) solution of
(1S,4S)-2,2-dimethyl-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate
(11.6 g, 41.1 mmol) in THF (110 mL) was added MeMgBr (3.0 M in THF,
16.5 mL, 49.5 mmol) at such a rate the internal temperature did not
increase above -30.degree. C. The reaction mixture was stirred for
15 min at -40.degree. C., quenched with saturated aqueous ammonium
chloride (200 mL), and warmed to room temperature. EtOAc (110 mL)
was added, the layers separated, and the aqueous layer was
extracted a second time with EtOAc (110 mL). The organic layers
were combined, dried over MgSO.sub.4, filtered, absorbed on silica,
and purified by silica gel chromatography to afford a mixture of
methyl
(1S,4S)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohex-
anecarboxylate and methyl
(1S,4S)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2,2-dimethylcyclohex-
anecarboxylate. Further purification was performed by SFC to afford
the single diastereomers.
[0243] Characterization data for Peak 1 from SFC: MS ESI calc'd.
for C.sub.15H.sub.24NO.sub.3S [M+H].sup.+ 298. found 298. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.68 (d, J=3.3 Hz, 1H), 7.50
(d, J=3.2 Hz, 1H), 5.71 (s, 1H), 3.53 (s, 3H), 1.98 (dd, J=3.9,
12.5 Hz, 1H), 1.89 (tt, J=3.3, 12.3 Hz, 1H), 1.83-1.75 (m, 1H),
1.65-1.49 (m, 2H), 1.42 (s, 3H), 1.14 (t, J=12.7 Hz, 114),
1.08-1.01 (m, 1H), 0.98-0.88 (m, 1H), 0.84 (s, 3H), 0.77 (s,
3H).
[0244] Characterization data for Peak 2 from SFC: MS ESI calc'd.
for C.sub.15H.sub.24NO.sub.3S [M+H].sup.+ 298. found 298. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 7.68 (d, J=3.3 Hz, 1H), 7.51
(d, J=3.3 Hz, 1H), 5.71 (s, 1H), 3.53 (s, 3H), 1.98 (dd, J=3.9,
12.4 Hz, 1H), 1.86 (tt, J=3.2, 12.5 Hz, 1H), 1.58-1.51 (m, 1H),
1.51 (s, 2H), 1.43 (s, 3H), 1.41-1.33 (m, 1H), 1.16-1.06 (m, 1H),
0.93 (t, J=12.3 Hz, 1H), 0.90 (s, 314), 0.83 (s, 3H).
Intermediate 14. Ethyl
4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2-methylcyclohexanecarboxylate
##STR00040##
[0246] Step 1:
[0247] To a cooled (0.degree. C.) suspension of
(methoxymethyl)triphenylphosphonium chloride (155 g, 452 mmol) in
THF (700 mL) was added potassium tert-butoxide (1.0 M in THF, 452
mL, 452 mmol) at such a rate that the internal temperature did not
exceed 7.degree. C. The mixture was stirred for 1 hour at 0.degree.
C., and then a solution of ethyl
2-methyl-4-oxocyclohexanecarboxylate (64 g, 347 mmol) in THF (150
mL) was added via canula at such a rate that the internal
temperature did not exceed 7.degree. C. The mixture was then slowly
warmed to room temperature and stirred for 14 hours. The reaction
mixture was then cooled to 10.degree. C. and diluted with water
(200 mL) followed by 6 M HCl (500 mL). The resulting mixture was
stirred for 3 hours, and then diluted with additional water (400
mL) and EtOAc (700 mL). The organic layer was separated, and the
aqueous layer was extracted a second time with EtOAc (700 mL). The
organic layers were combined, dried over MgSO.sub.4, filtered,
absorbed on silica gel, and purified by silica gel chromatography
to afford ethyl 4-formyl-2-methylcyclohexanecarboxylate, which was
used immediately in the subsequent step.
[0248] To a cooled solution of iPrMgCl--LiCl (1.3 M in THF, 187 mL,
243 mmol) at -5.degree. C. was added thiazole (17.4 mL, 243 mmol)
at such a rate that the internal temperature did not exceed
5.degree. C. The resulting slurry was warmed to 15.degree. C. over
15 minutes, and then cooled to -10.degree. C. To the reaction
mixture was added ethyl 4-formyl-2-methylcyclohexanecarboxylate (41
g, 207 mmol) as a solution in THF (100 mL) at such a rate the
internal temperature did not exceed 5.degree. C. The reaction
mixture was stirred for 30 minutes at 0.degree. C., and then
quenched with water (100 mL) and diluted with EtOAc (500 mL) and 1N
HCl (500 mL). The organic layer was separated, and the aqueous
layer extracted again with EtOAc (700 mL). The organic layers were
combined, dried over MgSO.sub.4, filtered, and concentrated under
reduced pressure. The residue was diluted with DCM (500 mL), and to
this mixture was added Dess-Martin periodinane (88 g, 208 mmol).
During the addition, the temperature was controlled such that the
internal temperature did not exceed 35.degree. C. After 1 hour, the
reaction mixture was cooled to room temperature and then diluted
with saturated aqueous NaHCO.sub.3 (600 mL), aqueous 5% sodium
sulfite (600 mL), and dichloromethane (600 mL). The heterogeneous
mixture was stirred until both layers were clear. The layers were
separated and the aqueous layer was extracted a second time with
dichloromethane (600 mL). The organic layers were combined, dried
over MgSO.sub.4, filtered, absorbed on silica, and purified by
silica gel chromatography to afford ethyl
2-methyl-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate. MS ESI
calc'd. for C.sub.14H.sub.20NO.sub.3S [M+H].sup.+ 282. found
282.
[0249] Step 2:
[0250] To a solution of ethyl
2-methyl-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate (2.8 g,
10 mmol) in THF (28 mL) at -40.degree. C. was added MeMgBr (3.0 M
in THF, 4.0 mL, 12 mmol) at such a rate the internal temperature
did not exceed -30.degree. C. The reaction mixture was stirred for
15 minutes at -40.degree. C., and was then quenched with saturated
aqueous ammonium chloride (50 mL) and warmed to room temperature.
EtOAc (20 mL) was added, the layers separated, and the aqueous
layer was extracted a second time with EtOAc (50 mL). The organic
layers were combined, dried over MgSO.sub.4, filtered, absorbed on
silica, and purified by silica gel chromatography to afford ethyl
4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-2-methylcyclohexanecarboxylate.
[0251] The mixture of stereoisomers were separated into 4 fractions
in order of increasing elution time by SFC (ES Industries GreenSep
Pyridyl Amide, 21.times.250 mm, 5 micron, 5% MeOH/95% CO.sub.2, 50
mL/min). These 4 fractions were then separated further using the
following conditions (Chiralpak AD-H 21.times.250 mm, 5 micron, 220
nm UV, 100 bar outlet pressure, 70 mL/min. The respective solvents
used are shown in the diagram below:
Intermediate 15:
(4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidin-2-one
(4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidin-2-one
##STR00041##
[0253] Step 1:
[0254] To a solution of thiazole (3.13 mL, 44 mmol) in THF (50 mL)
at -78.degree. C. was added nBuLi at such a rate that the internal
temperature did not exceed -65.degree. C. The reaction mixture was
stirred for 15 minutes, and then a solution of
(4R)-4-acetyl-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one (10
g, 38.3 mmol) in THF (50 mL) was added via canula at such a rate
that the internal temperature did not exceed -65.degree. C. The
mixture was stirred for 1 hour, quenched with saturated aqueous
ammonium chloride (50 mL), and warmed to room temperature. EtOAc
(50 mL) and water (50 mL) were added. The layers were separated,
and the aqueous layer was extracted a second time with EtOAc (50
mL). The organic layers were combined, dried over MgSO.sub.4,
filtered, absorbed on silica, and purified by silica gel
chromatography to afford
(4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1-(4-methoxyphe-
nyl)ethyl]pyrrolidin-2-one and
(4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1(4-methoxyphen-
yl)ethyl]pyrrolidin-2-one.
[0255] Characterization data for the less polar diastereomer,
(4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1-(4-methoxyphe-
nyl)ethyl]pyrrolidin-2-one: MS ESI calc'd. for
C.sub.18H.sub.23N.sub.2O.sub.3S [M+H].sup.+ 347. found 347. .sup.1H
NMR (600 MHz, DMSO-d.sub.6) .delta. 7.67 (d, J=3.2 Hz, 1H), 7.51
(d, =3.2 Hz, 1H), 7.00 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H),
6.08 (s, 1H), 5.10 (q, J=7.1 Hz, 1H), 3.70 (s, 3H), 3.35 (t, J=9.4
Hz, 1H), 2.89 (dd, J=9.8, 7.1 Hz, 1H), 2.82-2.72 (m, 1H), 2.43 (dd,
J=16.9, 8.2 Hz, 1H), 2.00 (dd, J=16.9, 9.8 Hz, 1H), 1.37-1.35 (m,
6H).
[0256] Characterization data for the more polar diastereomer,
(4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1-(4-methoxyphe-
nyl)ethyl]pyrrolidin-2-one: MS ESI calc'd. for
C.sub.18H.sub.23N.sub.2O.sub.3S [M+H].sup.+ 347. found 347. .sup.1H
NMR (600 MHz, DMSO-d.sub.6) .delta. 7.66 (d, J=3.2 Hz, 1H), 7.51
(d, J=3.2 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H),
6.08 (s, 1H), 5.14 (dd, J=14.2, 7.0 Hz, 1H), 3.70 (s, 3H),
2.99-2.90 (m, 1H), 2.88-2.78 (m, 2H), 2.40-2.30 (m, 2H), 1.33 (s,
3H), 1.30 (d, J=7.1 Hz, 3H).
[0257] Step 2:
[0258] A solution of
(4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1-(4-methoxyphe-
nyl)ethyl]pyrrolidin-2-one (3.6 g, 10.4 mmol) in TFA (10 mL) was
heated to 70.degree. C. for 5 hours. The reaction mixture was
cooled to room temperature, diluted with IPA (30 mL), and stirred
until the color dissipated. The reaction mixture was then absorbed
on silica gel and purified by silica gel chromatography to afford
(4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidin-2-one.
MS ESI calc'd. for C.sub.9H.sub.13N.sub.2O.sub.2S [M+H].sup.+ 213.
found 213. .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 7.68 (d,
J=3.2 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.39 (s, 1H), 6.10 (s, 1H),
3.25 (t, J=9.2 Hz, 1H), 3.19 (dd, J=9.6, 7.4 Hz, 1H), 2.91-2.81 (m,
1H), 2.20 (dd, J=16.7, 8.6 Hz, 1H), 1.77 (dd, J=16.7, 9.6 Hz, 1H),
1.43 (s, 3H).
[0259] Step 3:
[0260] A solution of
(4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1-(4-methoxyphe-
nyl)ethyl]pyrrolidin-2-one (3.6 g, 10.4 mmol) in TFA (10 mL) was
heated to 70.degree. C. for 5 hours. The reaction mixture was
cooled to room temperature, diluted with IPA (30 mL), and stirred
until the color dissipated. The reaction mixture was then absorbed
on silica gel and purified by silica gel chromatography to afford
(4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidin-2-one.
MS ESI calc'd. for C.sub.9H.sub.13N.sub.2O.sub.2S [M+H].sup.+ 213.
found 213. .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 7.69 (d,
J=3.2 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.35 (s, 1H), 6.12 (s, 1H),
3.08 (dd, J=9.1, 7.3 Hz, 1H), 2.96-2.86 (m, 1H), 2.82 (t, J=9.0 Hz,
1H), 2.22 (dd, J=16.8, 8.7 Hz, 1H), 2.14 (dd, J=16.8, 9.6 Hz, 1H),
1.42 (s, 3H).
Example 1
racemic
trans-4-[1-(5-{6-[(4-Cyclopropylpyridin-2-yl)amino]-4-methylpyridi-
n-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic
acid,
trans-4-[(1R)-1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin--
2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic acid,
and
trans-4-[(1S)-1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin--
2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic
acid
##STR00042##
[0262] Step 1:
[0263] A dry round bottom flask was charged with
trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.00 g, 10.74
mmol) and the reaction vessel was placed under an atmosphere of
argon (3.times. vacuum/argon cycle). Dichloromethane (11 mL) was
added followed by DMF (0.01 mL, 0.129 mmol). The reaction was
cooled to 0.degree. C. in an ice bath, then oxalyl chloride (1.00
mL, 11.42 mmoles) was added drop-wise. The ice bath was removed
after 1 hour and the reaction was stirred at ambient temperature
for 14 hours as gradual gas evolution occurred.
[1,1'-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (236.0
mg, 0.322 mmol) was then added to the reaction flask followed by
tetrahydrofuran (11 mL) then a solution of diethylzinc in
tetrahydrofuran (1.0 M, 12.9 mL, 12.9 mmol). The reaction was
stirred at ambient temperature for two hours and was then poured
into cold saturated aqueous ammonium chloride (100 mL). The
resulting biphasic solution was diluted with diethyl ether (100
mL). The organic phase was separated and dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (0-100% ethyl
acetate/hexanes) to afford methyl
trans-4-propanoylcyclohexanecarboxylate as a clear oil. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 3.67 (s, 3H), 2.47 (q, J=7.3 Hz, 2H),
2.40-2.21 (m, 2H), 2.12-2.00 (m, 2H), 1.94 (d, J=13.9 Hz, 2H),
1.53-1.20 (m, 4H), 1.03 (t, J=7.3 Hz, 3H).
[0264] Step 2:
[0265] Isopropyl magnesium chloride lithium chloride (1.3 M in THF,
6.66 mL, 8.66 mmol) was added drop-wise to a solution of thiazole
(0.675 mL, 9.44 mmol) in THF (5 mL) at 0.degree. C. The reaction
was stirred for 30 minutes and the ice bath was removed. Stirring
was then continued for 10 minutes before the reaction was re-cooled
in an acetone/dry ice bath, then a solution of methyl
trans-4-propanoylcyclohexanecarboxylate (1.56 g, 7.87 mmol) in THF
(15 mL) was transferred in via cannula. The reaction was stirred
for 1 hour and the cooling bath was removed. Once warming was
complete (.about.1 hour) the reaction was diluted with saturated
aqueous ammonium chloride (75 mL) and the resulting biphasic
mixture was transferred to a separatory funnel. The organic phase
was diluted with ethyl acetate (125 mL). The organic phase was
separated, dried over magnesium sulfate, filtered and concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (0-100% ethyl acetate/hexanes) to afford
trans-methyl
4-[1-hydroxy-1-(1,3-thiazol-2-yl)propyl]cyclohexanecarboxylate. MS
ESI calc'd. for C.sub.14H.sub.22NO.sub.3S [M+H].sup.+ 284. found
284. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.70 (d, J=3.3 Hz,
1H), 7.49 (d, J=3.3 Hz, 1H), 3.53 (s, 3H), 2.07 (t, J=12.1 Hz, 1H),
1.95-1.63 (m, 4H), 1.44-1.06 (m, 6H), 1.01-0.81 (m, 2H), 0.65 (t,
J=7.3 Hz, 3H).
[0266] Step 3:
[0267]
6-Bromo-N-(4-cyclopropylpyridin-2-yl)-4-methylpyridin-2-amine (263
mg, 0.865 mmol), trans-methyl
4-[1-hydroxy-1-(1,3-thiazol-2-yl)propyl]cyclohexanecarboxylate (245
mg, 0.865 mmol), pivalic acid (151 .mu.l, 1.297 mmol), potassium
carbonate (358 mg, 2.59 mmol), .pi.-allyl palladium(II)chloride
dimer (31.6 mg, 0.086 mmol) and butyl di-1-adamantylphosphine (124
mg, 0.346 mmol) were combined and the reaction flask was put under
inert atmosphere (3.times. vacuum/argon cycle) then degassed
dimethylacetamide (2 mL) was added. The reaction was heated to
100.degree. C. for 5 hours, then cooled to room temperature and
poured into diethyl ether (100 mL). The resulting solution was
transferred to a separatory funnel and sequentially washed with
water (3.times.50 mL) and sodium bicarbonate (50 mL), dried over
magnesium sulfate, filtered and concentrated under reduced
pressure. The resulting crude oil was purified by silica gel
chromatography (0-100% ethyl acetate/hexanes) to afford methyl
trans-4-[l-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-
-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylate as a
yellow foam. MS ESI calc'd. for C.sub.28H.sub.35N.sub.4O.sub.3S
[M+H].sup.+ 507. found 507. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.12-8.04 (m, 2H), 7.71 (s, 1H), 7.23 (s, 1H), 7.05 (s,
1H), 6.86 (s, 1H), 6.66 (d, J=5.2 Hz, 1H), 3.64 (s, 3H), 2.35 (s,
3H), 2.28-2.16 (m, 1H), 2.16-1.86 (m, 811), 1.51-1.30 (m, 3H), 1.26
(t, J=7.1 Hz, 1H), 1.21-1.06 (m, 3H), 1.03-0.93 (m, 2H), 0.83 (t,
J=7.2 Hz, 3H).
[0268] Step 4:
[0269] To a flask containing methyl
trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-
-1,3-thiazol-2-yl)-1-hydroxypropyl]-cyclohexanecarboxylate (198 mg,
0.391 mmol) and potassium hydroxide (88 mg, 1.563 mmol) was added
methanol (1 mL) and water (1 mL). The reaction vessel was sealed
and heated to 80.degree. C. for a period of 14 hours. After cooling
the reaction, aqueous hydrochloric acid (1.0 M, 1.56 mL, 1.56 mmol)
was added. The cloudy solution was diluted with additional water
(10 mL) and stirring was continued for one hour. Chloroform and
isopropanol (4:1; 20 mL total) were added and the biphasic mixture
was transferred to a separatory funnel. The organic phase was
separated, dried over sodium sulfate, filtered and concentrated
under reduced pressure to yield
trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-
-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic acid. MS
ESI calc'd. for C.sub.27H.sub.33N.sub.4O.sub.3S [M+H].sup.+ 493.
found 493. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.60-10.74
(br s, 1H), 8.48 (s, 1H), 8.27 (s, 1H), 7.75-7.29 (m, 2H), 7.26 (m,
2H), 5.68-5.47 (m, 1H), 2.42 (s, 3H), 2.29-2.12 (m, 1H), 2.12-1.84
(m, 7H), 1.84-1.73 (m, 1H), 1.54-1.42 (m, 1H), 1.43-1.13 (m, 6H),
1.13-0.97 (m, 3H), 0.88 (t, J=7.3 Hz, 3H). rhSyk activity=+++.
[0270] Two enantiomers were separated by chiral super critical
fluid chromatography (Chiral Technology AS-H, 2.1.times.25 cm, 5
uM, 3/1 MeOH/CO.sub.2+0.25% TFA, Flow Rate: 70 mL/min, 10 min run
time, WL: 220 nm). Elution was observed at 7.03 min and 8.08 min.
Pooled fractions of each peak were concentrated under reduced
pressure.
[0271] Enantiomer 1 (retention time=7.03 min): MS ESI calc'd. for
C.sub.27H.sub.33N.sub.4O.sub.3S [M+H].sup.+ 493. found 493. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) spectrum was consistent with the
.sup.1H NMR spectrum of the racemic material. rhSyk
activity=+++.
[0272] Enantiomer 2 (retention time=8.08 min): MS ESI calc'd. for
C.sub.27H.sub.33N.sub.4O.sub.3S [M+H].sup.+ 493. found 493. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) spectrum was consistent with the
.sup.1H NMR spectrum of the racemic material. rhSyk
activity=+++.
Example 2
trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}--
1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxamide,
trans-4-[(1R)-1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin--
2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxamide,
trans-4-[(1S)-1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin--
2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxamide
##STR00043##
[0274] To a flask containing racemic
trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-
-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylic acid (25
mg, 0.051 mmol) was added
0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (25.1 mg, 0.066 mmol) and ammonium chloride
(10.9 mg, 0.203 mmol). DMF (1 mL) and N,N-diisopropylethylamine
(0.089 mL, 0.507 mmol) were added and the reaction was sealed and
stirred for 2 hours. Methanol (0.1 mL) was then added to quench the
reaction and the resulting solution was filtered. The filtrate was
purified by reversed phase HPLC (10-100% acetonitrile/water with
0.1% TFA). The fractions containing desired product were pooled,
frozen and concentrated to dryness on a lyophilizer to afford
trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-
-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxamide. MS ESI
calc'd. for C.sub.27H.sub.34N.sub.5O.sub.2S [M+H].sup.+ 492. found
492. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.31 (s, 1H),
8.49 (s, 1H), 8.30 (d, J=6.4 Hz, 1H), 7.53 (s, 1H), 7.38 (s, 1H),
7.15 (s, 1H), 7.04 (d, J=6.4 Hz, 1H), 6.94 (s, 1H), 6.68 (s, 1H),
5.84-5.30 (m, 1H), 2.43 (s, 3H), 2.30-2.15 (m, 1H), 2.07-1.87 (m,
4H), 1.87-1.67 (m, 3H), 1.54-1.42 (m, 1H), 1.42-1.18 (m, 6H),
1.12-0.93 (m, 3H), 0.79 (t, J=7.3 Hz, 3H) ppm. rhSyk=+++.
[0275] The procedure above was used on the enantiopure acids
obtained from chiral SFC resolution of the racemic starting
material above (Example 1, Step 4).
[0276] Starting with (Example 1, Step 4, Enantiomer 1, R.sub.t=7.03
min): MS ESI calc'd. for C.sub.27H.sub.34N.sub.5O.sub.2S
[M+H].sup.+ 492. found 492. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
spectrum was consistent with the .sup.1H NMR spectrum of the
racemic material. rhSyk activity=+++. Starting with (Example 1,
Step 4, Enantiomer 2, R.sub.t=8.08 min): MS ESI calc'd. for
C.sub.27H.sub.34N.sub.5O.sub.2S [M+H].sup.+ 492. found 492. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) spectrum was consistent with the
.sup.1H NMR spectrum of the racemic material. rhSyk
activity=+++.
Example 3
trans-4-{(1R or
1S)-1-Hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid
(Enantiomer 2)
##STR00044##
[0278] Step 1:
[0279] To a flask were added cis-cyclohexane-1,4-dicarboxylic acid
(20 g, 116 mmol), n-butyl formate (581 ml, 5066 mmol), Dowex
50W.times.2 resin (87 grams), and octane (484 ml). The reaction
mixture was heated to 110.degree. C. overnight and then cooled and
filtered. The resin was washed with 300 mL 1:1 hexane:EtOAc. The
filtrate was concentrated and then taken up in toluene and
re-concentrated. The resulting residue was dissolved in
dichloromethane (119 ml) and then thionyl chloride (11.51 ml, 158
mmol) was added. The reaction mixture was heated to 38.degree. C.
overnight and then concentrated. The residue was taken up in DCM
and re-concentrated (3.times.) to remove residual HCl. The
resulting residue was dissolved in 1,4-dioxane (413 ml) and
degassed with Ar for 30 minutes. Palladium (II) acetate (0.696 g,
3.10 mmol) was added and the mixture was degassed for an additional
30 minutes. Dimethyl zinc (2 M in toluene, 31.0 ml, 62.0 mmol) was
added. The system was placed under argon through 3 cycles of
evacuation and argon flushing then reacted at 38.degree. C.
overnight. The reaction mixture was cooled and diluted with water.
The resulting mixture was filtered through a CELITE plug and then
the solid was washed with EtOAc. The filtrate was concentrated and
purified by column chromatography on silica gel (0-30% ethyl
acetate/hexanes) to afford butyl
cis-4-acetylcyclohexanecarboxylate. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 4.07 (t, J=6.6 Hz, 2H), 2.54-2.48 (m, 1H),
2.44-2.38 (m, 1H), 2.13 (s, 3H), 2.01-1.93 (m, 2H), 1.81-1.57 (m,
9H), 1.41-1.32 (m, 2H), 0.92 (t, J=7.5 Hz, 3H).
[0280] Step 2:
[0281] A solution of thiazole (800 mg, 9.40 mmol) in THF (94 mL)
was cooled to -78.degree. C. n-BuLi (2.5 M in THF, 3759 .mu.l, 9.40
mmol) was added and the solution was stirred for 30 minutes at
-78.degree. C. Butyl cis-4-acetylcyclohexanecarboxylate (2552 mg,
11.28 mmol) in THF (5 mL) was added in one portion and the solution
was stirred for one hour at -78.degree. C. The reaction was diluted
with water and then warmed to room temperature. The mixture was
extracted with ethyl acetate and the organic layer was dried over
magnesium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (5-30% ethyl acetate/hexanes) to afford cis-butyl
4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate. MS
ESI calc'd. for C.sub.16H.sub.25NO.sub.3S [M+H.sup.+] 312. found
312.
[0282] Step 3:
[0283] To a vial were added 2,6-dibromo-4-methylpyridine (121 mg,
0.482 mmol), cis-butyl
4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate (75
mg, 0.241 mmol), potassium carbonate (100 mg, 0.722 mmol), pivalic
acid (5.59 .mu.l, 0.048 mmol),
tetrakis(triphenylphosphine)palladium(0) (11.1 mg, 9.63 .mu.mol)
and N,N-dimethylacetamide (760 .mu.l). The vial was sealed and
placed under argon through 3 cycles of evacuation and argon
flushing then reacted at 80.degree. C. overnight. The resulting
mixture was cooled, diluted with ethyl acetate, filtered through a
plug of CELITE and concentrated. The residue was purified by column
chromatography on silica gel (0-100% ethyl acetate/hexanes) to
afford racemic-cis-butyl
4-{1-[5-(6-bromo-4-methylpyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}--
cyclohexanecarboxylate.
[0284] Two enantiomers were separated by chiral super critical
fluid chromatography (Chiral Technology IC-H, 2.1.times.25 cm, 5
uM, 70/30 ethanol/CO.sub.2, Flow Rate: 70 mL/min, 8 min run time,
WL: 220 nm). Elution was observed at 5.20 min and 6.08 min. Pooled
fractions of each peak were concentrated under reduced
pressure.
[0285] Enantiomer 1 (retention time 5.20 min): MS ESI calc'd. for
C.sub.22H.sub.29BrF.sub.3N.sub.2O.sub.3S [M+H.sup.+] 481 and 483.
found 481 and 483.
[0286] Enantiomer 2 (retention time 6.08 min): MS ESI calc'd. for
C.sub.22H.sub.29BrF.sub.3N.sub.2O.sub.3S [M+H.sup.+] 481 and 483.
found 481 and 483.
[0287] Step 4:
[0288] To a vial were added 4-(trifluoromethyl)pyridin-2-amine (10
mg, 0.062 mmol), cis-butyl
4-{1-[5-(6-bromo-4-methylpyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}--
cyclohexanecarboxylate (Step 3, Enantiomer 1, R.sub.t=5.20 min)
(14.9 mg, 0.031 mmol), palladium(II) acetate (0.7 mg, 3 .mu.mol),
Xantphos (2.7 mg, 4.6 gimp, cesium carbonate (20.1 mg, 0.062 mmol)
and 1,4-dioxane (308 .mu.l). The vial was sealed and placed under
argon through 3 cycles of evacuation and argon flushing followed by
heating at 100.degree. C. for 2 hr and 30 minutes. The mixture was
cooled, diluted with EtOAc, filtered through a plug of CELITE and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (0-100% ethyl acetate/hexanes)
to afford butyl 4-{(1R or
1S)-1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylate. MS ESI
calc'd. for C.sub.28H.sub.33F.sub.3N.sub.4O.sub.3S [M+H.sup.+] 563.
found 563.
[0289] Step 5:
[0290] To a vial were added butyl 4-{(1R or
1S)-1-[5-(6-bromo-4-methylpyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}-
cyclohexanecarboxylate (10 mg, 0.018 mmol), MeOH (178 .mu.l) and
NaOH (1 M in water, 89 .mu.l, 0.089 mmol). The vial was sealed and
heated in a microwave for 10 minutes at 100.degree. C. An
additional 25 uL NaOH was added and then heated in a microwave for
20 minutes. Then, the pH was adjusted to 3-4 with 1 M aqueous HCl.
The solution was diluted with 10% IPA/CHCl.sub.3 and washed with
water and brine. The organic layer was separated by passing through
a hydrophobic membrane cartridge and concentrated to afford
trans-4-{(1R or
1S)-1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid. MS
ESI calc'd. for C.sub.24H.sub.25F.sub.3N.sub.4O.sub.3S [M+H.sup.+]
507. found 507. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.19
(s, 1H), 8.64 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.26 (s, 1H), 7.34
(s, 1H), 7.21 (d, J=5.0 Hz, 1H), 7.08 (s, 1H), 2.31 (s, 3H),
2.06-1.67 (m, 3H), 1.67-1.34 (m, 5H), 1.31-0.96 (m, 5H). rhSyk
activity=+++.
Example 4
trans-4-{(1R or
1S)-1-Hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid
(Enantiomer 1)
##STR00045##
[0292] Step 1:
[0293] To a vial were added 4-(trifluoromethyl)pyridin-2-amine (8
mg, 0.049 mmol), cis-butyl
4-{1-[5-(6-bromo-4-methylpyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}--
cyclohexanecarboxylate (Example 3, Step 3, Enantiomer 2,
R.sub.t=6.08 min) (11.9 mg, 0.025 mmol), palladium(II) acetate (0.6
mg, 2.47 .mu.mol), Xantphos (2.1 mg, 3.7 .mu.mol), cesium carbonate
(16.1 mg, 0.049 mmol) and 1,4-dioxane (2470). The vial was sealed
and placed under argon through 3 cycles of evacuation and argon
flushing then reacted at 100.degree. C. overnight. The resulting
mixture was cooled, diluted with EtOAc, filtered through a plug of
CELITE and concentrated. The residue was purified by column
chromatography on silica (0-100% ethyl acetate/hexanes) to afford
butyl 4-{(1R or
1S)-1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-p-
yridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylate. MS ESI
calc'd. for C.sub.28H.sub.33F.sub.3N.sub.4O.sub.3S [M+H.sup.+] 563.
found 563.
[0294] Step 2:
[0295] To a vial were added butyl 4-{(1R or
1S)-1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]ethyl}-cyclohexanecarboxylate (10 mg,
0.018 mmol), MeOH (178 .mu.l) and NaOH (1 M in water, 89 .mu.l,
0.089 mmol). The vial was sealed and placed under argon through 3
cycles of evacuation and argon flushing and then heated in a
microwave for 10 minutes at 100.degree. C. Then, the pH was
adjusted pH to 3-4 with 1M HCl. The solution was diluted with 10%
IPA/CHCl.sub.3 and washed with water and brine. The organic layer
was separated by passing through a hydrophobic membrane cartridge
and concentrated to afford trans-4-{(1R or
1S)-1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid. MS
ESI calc'd. for C.sub.24H.sub.25F.sub.3N.sub.4O.sub.3S [M+H+] 507.
found 507. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.18 (s,
1H), 8.64 (s, 1H), 8.48 (d, J=5.3 Hz, 1H), 8.26 (s, 1H), 7.34 (s,
1H), 7.20 (d, J=5.5 Hz, 1H), 7.08 (s, 1H), 2.31 (s, 3H), 2.15-1.72
(m, 3H), 1.72-1.32 (m, 5H), 1.31-0.87 (m, 5H). rhSyk
activity=+++.
Example 5
trans-4-[(1R or
1S)-1-(5-{6-[(5-Fluoro-4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiaz-
ol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid (Enantiomer
1)
##STR00046##
[0297] Step 1:
[0298] A solution of 5-fluoro-4-methylpyridin-2-amine (16.2 mg,
0.128 mmol), butyl
trans-4-{1-[5-(6-bromopyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}cycl-
ohexanecarboxylate (Intermediate 4, Step 2, Enantiomer 1,
R.sub.t=3.98 min) (57 mg, 0.122 mmol), Xantphos (10.6 mg, 0.018
mmol), cesium carbonate (79 mg, 0.244 mmol), and palladium(II)
acetate (2.7 mg, 0.012 mmol) in 1,4-dioxane (0.8 mL) under an argon
atmosphere was heated to 115.degree. C. for 1.5 hours. After
cooling to room temperature, the reaction mixture was partitioned
between ethyl acetate (20 mL) and saturated aqueous sodium
bicarbonate solution (10 mL). The layers were separated and the
organic layer was washed with brine, dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (25-45% ethyl
acetate/hexanes) to provide butyl trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiaz-
ol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate. MS ESI calc'd. for
C.sub.27H.sub.33FN.sub.4O.sub.3S [M+H].sup.+ 513. found 513.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.10 (s, 1H), 8.01 (s,
1H), 7.88 (d, J=5.8 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.20 (d, J=7.6
Hz, 1H), 7.17 (s, 1H), 7.07 (d, J=8.3 Hz, 1H), 4.04 (t, J=6.6 Hz,
2H), 3.03 (s, 1H), 2.38 (s, 3H), 2.24-2.17 (m, 1H), 2.10-1.98 (m,
3H), 1.83-1.75 (m, 1H), 1.73-1.67 (m, 1H), 1.65 (s, 3H), 1.62-1.56
(m, 2H), 1.48-1.38 (m, 2H), 1.40-1.32 (m, 2H), 1.32-1.25 (m, 1H),
1.23-1.15 (m, 1H), 0.91 (t, J=7.4 Hz, 3H).
[0299] Step 2:
[0300] To a solution of butyl trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiaz-
ol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate (54.7 mg, 0.107
mmol) in tetrahydrofuran (0.6 mL) and methanol (1.2 mL) was added
sodium hydroxide (1.0 M in water, 0.427 mL, 0.427 mmol). The
reaction mixture was heated in a microwave oven for 5 minutes at
110.degree. C. and then hydrochloric acid (2.0 M in water, 0.220
mL, 0.440 mmol) was added. The mixture was diluted with 10%
IPA:CHCl.sub.3 (25 mL), ethyl acetate (100 mL), and brine. The
layers were separated and the organic layer was washed with brine,
dried over sodium sulfate, filtered, and concentrated under reduced
pressure to provide trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiaz-
ol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid. MS ESI calc'd.
for C.sub.23H.sub.25FN.sub.4O.sub.3S [M+H].sup.+ 457. found 457.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.95 (br s, 1H), 9.74
(s, 1H), 8.26 (s, 1H), 8.15 (d, J=6.1 Hz, 1H), 8.11 (s, 1H), 7.66
(t, J=7.9 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.23 (d, J=8.2 Hz, 1H),
5.82 (s, 1H), 2.32 (s, 3H), 2.07-1.94 (m, 1H), 1.92-1.83 (m, 3H),
1.67-1.60 (m, 1H), 1.54-1.48 (m, 1H), 1.48 (s, 3H), 1.26-1.14 (m,
3H), 1.08-1.02 (m, 1H). rhSyk activity=+++.
Example 6
trans-4-[(1R or
1S)-1-(5-{6-[(5-Fluoro-4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiaz-
ol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid (Enantiomer
2)
##STR00047##
[0302] Step 1:
[0303] A solution of 5-fluoro-4-methylpyridin-2-amine (15.6 mg,
0.124 mmol), butyl trans-4-{(1R or
1S)-1-[5-(6-bromopyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}cyclohexa-
necarboxylate (Intermediate 4, Step 2, Enantiomer 2, R.sub.t=4.76
min) (55 mg, 0.118 mmol), Xantphos (10.2 mg, 0.018 mmol), cesium
carbonate (77 mg, 0.235 mmol), and palladium(II) acetate (2.6 mg,
0.012 mmol) in 1,4-dioxane (0.8 mL) under an argon atmosphere was
heated to 115.degree. C. for 2 hours. After cooling to room
temperature, the reaction mixture was partitioned between ethyl
acetate (20 mL) and saturated aqueous sodium bicarbonate solution
(10 mL). The layers were separated and the organic layer was washed
with brine, dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by chromatography
on silica gel (25-45% ethyl acetate/hexanes) to provide butyl
trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiaz-
ol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate. MS ESI calc'd. for
C.sub.27H.sub.33FN.sub.4O.sub.3S [M+H].sup.+ 513. found 513.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.10 (s, 1H), 8.01 (s,
1H), 7.88 (d, J=5.7 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.20 (d, J=7.5
Hz, 1H), 7.17 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 4.04 (t, J=6.7 Hz,
2H), 3.03 (s, 1H), 2.38 (s, 3H), 2.22-2.16 (m, 1H), 2.10-1.96 (m,
3H), 1.83-1.77 (m, 1H), 1.69-1.64 (m, 1H), 1.65 (s, 3H), 1.62-1.55
(m, 2H), 1.48-1.39 (m, 2H), 1.39-1.32 (m, 2H), 1.32-1.27 (m, 1H),
1.21-1.15 (m, 1H), 0.91 (t, J=7.4 Hz, 4H).
[0304] Step 2:
[0305] To a solution of butyl trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]pyridin-2-yl}-1,3-thiaz-
ol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate (48.5 mg, 0.095
mmol) in tetrahydrofuran (0.6 mL) and methanol (1.2 mL) was added
sodium hydroxide (1.0 M in water, 0.378 mL, 0.378 mmol). The
reaction mixture was heated in a microwave oven for 5 minutes at
110.degree. C. and then hydrochloric acid (2.0 M in water, 0.192
mL, 0.384 mmol) was added. The resulting suspension was diluted
with water and filtered to provide trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]pyridin-2-yl}hydroxyeth-
yl]cyclohexanecarboxylic acid. MS ESI calc'd. for
C.sub.23H.sub.25FN.sub.4O.sub.3S [M+H].sup.+ 457. found 457.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.95 (br s, 1H), 9.74
(s, 1H), 8.26 (s, 1H), 8.15 (d, J=5.7 Hz, 1H), 8.11 (s, 1H), 7.66
(t, J=7.9 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H),
5.82 (s, 1H), 2.34 (s, 1H), 2.32 (s, 3H), 2.07-1.94 (m, 1H),
1.91-1.83 (m, 3H), 1.67-1.61 (m, 1H), 1.53-1.47 (m, 1H), 1.48 (s,
3H), 1.26-1.14 (m, 3H), 1.08-1.02 (m, 1H). rhSyk activity=+++.
Example 7
trans-4-{(1R or
1S)-1-Hydroxy-1-[5-(6-[4-(trifluoromethyl)pyridin-2-yl]amino
pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid
(Enantiomer 1)
##STR00048##
[0307] Step 1:
[0308] A solution of 4-(trifluoromethyl)pyridin-2-amine (20.8 mg,
0.128 mmol), butyl trans-4-{(1R or
1S)-1-[5-(6-bromopyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}-cyclohex-
anecarboxylate (Intermediate 4, Step 2, Enantiomer 1, R.sub.t=3.98
min) (57 mg, 0.122 mmol), Xantphos (10.6 mg, 0.018 mmol), cesium
carbonate (79 mg, 0.244 mmol), and palladium(II) acetate (2.7 mg,
0.012 mmol) in 1,4-dioxane (0.8 mL) under an argon atmosphere was
heated to 115.degree. C. for 2 hours. After cooling to room
temperature, the reaction mixture was partitioned between ethyl
acetate (20 mL) and saturated aqueous sodium bicarbonate solution
(10 mL). The layers were separated and the organic layer was washed
with brine, dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by chromatography
on silica gel (25-45% ethyl acetate/hexanes) to provide butyl
trans-4-{(1R or
1S)-1-hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-y-
l)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid. MS ESI
calc'd. for C.sub.27H.sub.31F.sub.3N.sub.4O.sub.3S [M+H].sup.+ 549.
found 549. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.61 (s, 1H),
8.41 (d, J=5.2 Hz, 1H), 8.10 (s, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.48
(s, 1H), 7.28 (d, J=7.5 Hz, 1H), 7.11 (d, J=4.9 Hz, 1H), 6.94 (d,
J=8.2 Hz, 1H), 4.04 (t, J=6.6 Hz, 2H), 3.20 (s, 1H), 2.22-2.16 (m,
1H), 2.10-1.98 (m, 3H), 1.79 (m, 1H), 1.69-1.64 (m, 1H), 1.65 (s,
3H), 1.62-1.57 (m, 3H), 1.49-1.39 (m, 2H), 1.38-1.33 (m, 1H),
1.32-1.24 (m, 1H), 1.21-1.18 (m, 1H), 0.91 (t, J=7.4 Hz, 3H).
[0309] Step 2:
[0310] To a solution of butyl trans-4-{(1R or
1S)-1-hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-y-
l)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid (59.6 mg,
0.109 mmol) in tetrahydrofuran (0.6 mL) and methanol (1.2 mL) was
added sodium hydroxide (1.0 M in water, 0.435 mL, 0.435 mmol). The
reaction mixture was heated in a microwave oven for 5 minutes at
110.degree. C. and then hydrochloric acid (2.0 M in water, 0.220
mL, 0.440 mmol) was added. The resulting mixture was diluted with
10% IPA:CHCl.sub.3 and brine and the layers were separated. The
aqueous layer was extracted with 10% IPA:CHCl.sub.3 and then the
combined organic layers were dried over sodium sulfate, filtered,
and concentrated under reduced pressure to afford trans-4-{(1R or
1S)-1-hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-y-
l)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid. MS ESI
calc'd. for C.sub.23H.sub.23F.sub.3N.sub.4O.sub.3S [M+H].sup.+ 493.
found 493. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.95 (s,
1H), 10.27 (s, 1H), 8.64 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.28 (s,
1H), 7.73 (t, J=7.9 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.26 (d, J=8.2
Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 5.75 (d, J=10.1 Hz, 1H), 2.01 (m,
1H), 1.94-1.82 (m, 2H), 1.64 (m, 1H), 1.53 (m, 1H), 1.48 (s, 3H),
1.24-1.14 (m, 4H), 1.02 (m, 1H). rhSyk activity=+++.
Example 8
trans-4-{(1R or
1S)-1-Hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-y-
l)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid (Enantiomer
2)
##STR00049##
[0312] Step 1:
[0313] A solution of 4-(trifluoromethyl)pyridin-2-amine (20.0 mg,
0.124 mmol), butyl trans-4-{(1R or
1S)-1-[5-(6-bromopyridin-2-yl)-1,3-thiazol-2-yl]-1-hydroxyethyl}cyclohexa-
necarboxylate (Intermediate 4, Step 2, Enantiomer 2, R.sub.t=4.76
min) (55 mg, 0.118 mmol), XANTPHOS (10.2 mg, 0.018 mmol), cesium
carbonate (77 mg, 0.235 mmol), and palladium(II) acetate (2.6 mg,
0.012 mmol) in 1,4-dioxane (0.8 mL) under an argon atmosphere was
heated to 115.degree. C. for 2 hours. After cooling to room
temperature, the reaction mixture was partitioned between ethyl
acetate (20 mL) and saturated aqueous sodium bicarbonate solution
(10 mL). The layers were separated and the organic layer was washed
with brine, dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by chromatography
on silica gel (25-45% ethyl acetate/hexanes) to provide butyl
trans-4-{(1R or
1S)-1-Hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-y-
l)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid. MS ESI
calc'd. for C.sub.27H.sub.31F.sub.3N.sub.4O.sub.3S [M+H].sup.+ 549.
found 549. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.61 (s, 1H),
8.41 (d, J=4.7 Hz, 1H), 8.10 (s, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.47
(s, 1H), 7.28 (d, J=7.0 Hz, 1H), 7.11 (d, J=4.3 Hz, 1H), 6.94 (d,
J=8.1 Hz, 1H), 4.04 (t, J=6.6 Hz, 2H), 3.20 (s, 1H), 2.22-2.17 (m,
1H), 2.10-1.98 (m, 3H), 1.82-1.76 (m, 1H), 1.70-1.65 (m, 1H), 1.65
(s, 3H), 1.62-1.57 (m, 3H), 1.48-1.39 (m, 2H), 1.38-1.33 (m, 1H),
1.32-1.24 (m, 1H), 1.20-1.14 (m, 1H), 0.91 (t, J=7.4 Hz, 3H).
[0314] Step 2: To a solution of butyl trans-4-{(1R or
1S)-1-hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-y-
l)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid (58.5 mg,
0.107 mmol) in tetrahydrofuran (0.6 mL) and methanol (1.2 mL) was
added sodium hydroxide (1.0 M in water, 0.427 mL, 0.427 mmol). The
reaction mixture was heated in a microwave oven for 5 minutes at
110.degree. C. and then hydrochloric acid (2.0 M in water, 0.215
mL, 0.430 mmol) was added. The resulting mixture was diluted with
10% IPA:CHCl.sub.3 and brine and the layers were separated. The
aqueous layer was extracted with 10% IPA:CHCl.sub.3 and then the
combined organic layers were dried over sodium sulfate, filtered,
and concentrated under reduced pressure to afford trans-4-{(1R or
1S)-1-hydroxy-1-[5-(6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-y-
l)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid. MS ESI
calc'd. for C.sub.23H.sub.23F.sub.3N.sub.4O.sub.3S [M+H].sup.+ 493.
found 493. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.95 (br s,
1H), 10.27 (s, 1H), 8.64 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.28 (s,
1H), 7.73 (t, J=7.9 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.26 (d, J=8.2
Hz, 1H), 7.22 (d, J=5.3 Hz, 1H), 5.76 (s, 1H), 2.02-1.95 (m, 1H),
1.94-1.92 (m, 2H), 1.66-1.61 (m, 1H), 1.54-1.49 (m, 1H), 1.48 (s,
3H), 1.24-1.14 (m, 4H), 1.05-0.99 (m, 1H). rhSyk activity=+++.
Example 9
Butyl
trans-4-[(1R)-1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-methy-
lpyridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate
and butyl
trans-4-[(1S)-1-(5-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-meth-
ylpyridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate
##STR00050##
[0316] Step 1:
[0317] Into a flask were added 2,6 dibromo-4-methyl pyridine (10.0
g, 40.0 mmol), sodium tert-butoxide (4.4 g, 46.0 mmol),
2-amino-4-methyl-5-fluoro pyridine (5.8 g, 45.8 mmol) and
1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.3
g, 1.9 mmol) followed by nitrogen sparged 1,4-dioxane (100 mL). The
slurry was evacuated and refilled with nitrogen three times and
then heated to 88.degree. C. for 5 hours. After cooling to
25.degree. C., ethyl acetate (100 mL) and water (20 mL) were added
and the layers were separated. The organic layer was washed with
10% aqueous sodium chloride solution (25 mL) and then concentrated
under reduced pressure. The residue was purified by chromatography
on silica gel (10-50% ethyl acetate/hexanes) to afford
N-(6-bromo-4-methylpyridine-2-yl)-5-fluoro-4-methylpyridine-2-amine.
1H NMR (600 MHz, DMSO-d.sub.6) .delta. 9.87 (s, 1H), 8.07 (d, J=0.8
Hz, 1H), 7.61 (s, 1H), 7.32 (d, J=5.6 Hz, 1H), 6.87 (s, 1H), 2.20
(s, 3H), 2.19 (s, 3H).
[0318] Step 2:
[0319] Into a flask were added butyl diadamantyl phosphine (0.133
g, 0.37 mmol), palladium(II) acetate (0.04 g, 2.2 mmol), potassium
carbonate (0.77 g, 5.6 mmol), pivalic acid (0.23 g, 2.2 mmol),
butyl
trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate
(0.69 g, 60.0 mmol), and
N-(6-bromo-4-methylpyridine-2-yl)-5-fluoro-4-methylpyridine-2-amine
(0.55 g, 1.86 mmol) followed by nitrogen sparged dimethyl acetamide
(4.4 mL). The slurry was evacuated and refilled with nitrogen three
times and then slowly heated to 130.degree. C. for 15 hours. The
slurry was cooled to 35.degree. C. and diluted with ethyl acetate
(100 mL). The slurry was then filtered through CELITE, washed with
10% aqueous NaCl (3.times.100 mL) and concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
(ethyl acetate/hexanes) to obtain racemic butyl
trans-4-[1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-methylpy-
ridine-2-yl}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate
as a foam. 1H NMR (600 MHz, DMSO-d.sub.6) .delta. 9.62 (s, 1H),
8.21 (s, 1H), 8.12 (d, J=5.8 Hz, 1H), 8.08 (s, 1H), 7.21 (s, 1H),
7.04 (s, 1H), 5.79 (s, 1H), 3.93 (t, J=6.5 Hz, 2H), 2.29 (s, 3H),
2.25 (s, 3H), 2.14-2.05 (m, 1H), 1.93-1.80 (m, 3H), 1.65-1.60 (m,
1H), 1.53-1.47 (m, 3H), 1.45 (s, 3H), 1.31-1.16 (m, 5H), 1.08-0.99
(m, 1H), 0.83 (t, J=7.4 Hz, 3H).
[0320] Two enantiomers were separated by chiral super critical
fluid chromatography (Chiral Technology AS-H, 2.1.times.25 cm, 5
uM, 20/80 ethanol/CO.sub.2, Flow Rate: 70 mL/min, 11 min run time,
WL: 275 nm). Elution was observed at 5.77 min and 7.36 min. Pooled
fractions of each peak were concentrated under reduced
pressure.
[0321] Enantiomer 1 (retention time=5.77 min): MS ESI calc'd. for
C.sub.28H.sub.35FN.sub.4O.sub.3S [M+H].sup.+ 527. found 527.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.65 (s, 1H), 8.24 (s,
1H), 8.15 (d, J=5.9 Hz, 1H), 8.10 (s, 1H), 7.24 (s, 1H), 7.06 (s,
1H), 5.82 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.31 (s, 3H), 2.27 (s,
3H), 2.14-2.08 (m, 1H), 1.95-1.80 (m, 3H), 1.68-1.63 (m, 1H),
1.57-1.48 (m, 3H), 1.48 (s, 3H), 1.33-1.14 (m, 5H), 1.08-1.01 (m,
1H), 0.85 (t, J=7.4 Hz, 3H). rhSyk activity=++
[0322] Enantiomer 2 (retention time=7.36 min) MS ESI calc'd. for
C.sub.28H.sub.35FN.sub.4O.sub.3S [M+H].sup.+ 527. found 527.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.65 (s, 1H), 8.24 (s,
1H), 8.14 (d, J=5.7 Hz, 1H), 8.10 (s, 1H), 7.24 (s, 1H), 7.06 (s,
1H), 5.82 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.31 (s, 3H), 2.27 (s,
3H), 2.11 (s, 1H), 1.95-1.80 (m, 3H), 1.68-1.63 (m, 1H), 1.57-1.48
(m, 3H), 1.48 (s, 3H), 1.33-1.17 (m, 5H), 1.05 (m, 1H), 0.85 (t,
J=7.4 Hz, 3H). rhSyk activity=++
Example 10
trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-methylpyridine-2-yl-
}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid
(Enantiomer 1)
##STR00051##
[0324] To a solution of butyl trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-methylpyridine-2-yl-
}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate (Example
9, Step 2, Enantiomer 1, R.sub.t=5.77 min) (725 mg, 1.377 mmol) in
tetrahydrofuran (8 mL) and methanol (16 mL) was added sodium
hydroxide (1.0 M in water, 5.51 mL, 5.51 mmol). The reaction
mixture was heated to 70.degree. C. for 90 minutes and then allowed
to cool to room temperature. Hydrochloric acid (2.0 M in water,
2.75 mL, 5.50 mmol) and water (30 mL) were added and the resulting
precipitate was collected by filtration. The solid was washed with
water (2.times.10 mL) and then dried under reduced pressure to give
trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-methylpyridine-2-yl-
}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate. MS ESI
calc'd. for C.sub.24H.sub.27FN.sub.4O.sub.3S [M+H].sup.+ 471. found
471. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.96 (br s, 1H),
9.65 (s, 1H), 8.24 (s, 1H), 8.14 (d, J=6.0 Hz, 1H), 8.10 (s, 1H),
7.24 (s, 1H), 7.06 (s, 1H), 5.81 (s, 1H), 2.31 (s, 3H), 2.27 (s,
3H), 2.04-1.98 (m, 1H), 1.94-1.82 (m, 3H), 1.66-1.61 (m, 1H),
1.53-1.48 (m, 1H), 1.48 (s, 3H), 1.28-1.14 (m, 3H), 1.07-1.02 (m,
1H). rhSyk activity=+++.
Example 11
trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-methylpyridine-2-yl-
}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid
(Enantiomer 2)
##STR00052##
[0326] To a solution of butyl trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-methylpyridine-2-yl-
}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate (Example
9, Step 2, Enantiomer 2, R.sub.t=7.36 min) (725 mg, 1.377 mmol) in
tetrahydrofuran (8 mL) and methanol (16 mL) was added sodium
hydroxide (1.0 M in water, 5.51 mL, 5.51 mmol). The reaction
mixture was heated to 70.degree. C. for 90 minutes and then allowed
to cool to room temperature. Hydrochloric acid (2.0 M in water,
2.75 mL, 5.50 mmol) and water (30 mL) were added and the resulting
precipitate was collected by filtration. The solid was washed with
water (2.times.10 mL) and then dried under reduced pressure to give
trans-4-[(1R or
1S)-1-(5-{6-[(5-fluoro-4-methylpyridine-2-yl)amino]-4-methylpyridine-2-yl-
}-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate. MS ESI
calc'd. for C.sub.24H.sub.27FN.sub.4O.sub.3S [M+H].sup.+ 471. found
471. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.96 (br s, 1H),
9.65 (s, 1H), 8.24 (s, 1H), 8.14 (d, J=6.0 Hz, 1H), 8.10 (s, 1H),
7.24 (s, 1H), 7.06 (s, 1H), 5.81 (s, 1H), 2.31 (s, 3H), 2.27 (s,
3H), 2.04-1.98 (m, 1H), 1.94-1.82 (m, 3H), 1.66-1.61 (m, 1H),
1.53-1.48 (m, 1H), 1.48 (s, 3H), 1.28-1.14 (m, 3H), 1.07-1.02 (m,
1H). rhSyk activity=+++.
Example 12
1-[5-(4-Methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-
-thiazol-2-yl]-1-(pyrrolidin-3-yl)ethanol
##STR00053##
[0328] Step 1:
[0329] Isopropylmagnesium chloride lithium chloride (1.3 M in
tetrahydrofuran, 0.6 mL, 0.780 mmol) was added dropwise at room
temperature to a flask containing a solution of thiazole (0.050 mL,
0.705 mmol) in tetrahydrofuran (5 mL) with a water bath around the
flask. After 40 min, tert-butyl 3-acetylpyrrolidine-1-carboxylate
(160 mg, 0.750 mmol) in tetrahydrofuran (5 mL) was added dropwise.
After stirring at room temperature for 35 min, the mixture was
diluted with saturated aqueous ammonium chloride and extracted with
ethyl acetate. The organic phase was washed with water and brine,
dried over sodium sulfate, and concentrated under reduced pressure.
The residue was purified by chromatography on silica gel (0-60%
ethyl acetate/hexane) to afford tert-butyl
3-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidine-1-carboxylate as
a 1:1 mix of diastereomers. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 7.69-7.55 (m, 1H, two sets of doublets overlap from two
diastereomers), 7.23-7.14 (m, 1H, two sets of doublets overlap from
two diastereomers), 3.59-2.98 (m, 4H), 2.80-2.60 (m, 1H), 1.98-1.70
(m, 2H), 1.59 (s, 3H), 1.45-1.30 (m, 9H, two sets of peaks overlap
from two diastereomers).
[0330] Step 2:
[0331] tert-Butyl
3-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidine-1-carboxylate
(100 mg, 0.335 mmol),
6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine
(112 mg, 0.337 mmol), butyl di-1-adamantylphosphine (25 mg, 0.070
mmol), tris(dibenzylideneacetone)dipalladium(0) (16.3 mg, 0.018
mmol), pivalic acid (0.018 mL, 0.157 mmol), potassium carbonate
(140 mg, 1.013 mmol) and N,N-dimethylacetamide (1 mL) were combined
and the mixture was evacuated and purged with nitrogen 3 times then
heated to 130.degree. C. for 7 hours. The mixture was filtered then
extracted with ethyl acetate. The organic phase was washed with
water and brine, dried over sodium sulfate, and concentrated under
reduced pressure to afford tert-butyl
3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)-pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxylate, which
was used in a subsequent step without further purification. MS ESI
calc'd. for C.sub.26H.sub.30F.sub.3N.sub.5O.sub.3S [M+H].sup.+ 550.
found 550.
[0332] Step 3:
[0333] Trifluoroacetic acid (0.4 mL, 5.19 mmol) was added to a
solution of tert-butyl
3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyr-
idin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxylate (100
mg, 0.182 mmol) in dichloromethane (0.8 mL). The mixture was
stirred at room temperature for 16 hours then concentrated under
reduced pressure. The residue was purified on reverse phase HPLC
(Sunfire prep C18 OBD 5 uM, acetonitrile/water+0.1% TFA) to afford
1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,-
3-thiazol-2-yl]-1-(pyrrolidin-3-yl)ethanol as a 1:1 mix of
diastereomers. MS ESI calc'd. for C.sub.21H.sub.22F.sub.3N.sub.5OS
[M+H].sup.+ 450. found 450. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 8.55 (d, J=5.6 Hz, 1H), 8.37 (d, 11-1, two singlets from
two diastereomers), 8.12 (s, 1H), 7.46 (s, 1H), 7.37 (d, J=5.5 Hz,
1H), 7.05 (s, 1H), 3.58-2.95 (m, 5H, two sets of peaks from two
diastereomers), 2.45 (s, 3H), 2.30-1.79 (m, 2H, two sets of peaks
from two diastereomers), 1.69 (d, 3H, two singlets from two
diastereomers). rhSyk activity=+++.
Example 13
3-{1-Hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyri-
din-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxamide
##STR00054##
[0335] To the solution of
1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,-
3-thiazol-2-yl]-1-(pyrrolidin-3-yl)ethanol (20 mg, 0.044 mmol, 1:1
mix of diastereomers) in tetrahydrofuran (0.4 mL) was added
potassium cyanate (25 mg, 0.308 mmol), water (1.2 mL) and HCl (2 M
in water, 0.14 mL, 0.280 mmol). The mixture was stirred at
55.degree. C. for 3 hours then cooled to room temperature. The
mixture was purified on reversed phase HPLC (Sunfire prep C18 OBD 5
uM, acetonitrile/water+0.1% TFA) to afford
3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyr-
idin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxamide as a
1:1 mixture of diastereomers. MS ESI calc'd. for
C.sub.22H.sub.23F.sub.3N.sub.6O.sub.2S [M+H].sup.+ 493. found 493.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.65-8.60 (m, 1H, two
sets of doublets overlap from two diastereomers), 8.39 (d, 1H, two
singlets from two diastereomers), 7.86 (s, 1H), 7.51 (d, 1H, two
singlets from two diastereomers), 7.46-7.42 (m, 1H, two sets of
doublets overlap from two diastereomers), 7.05 (s, 1H), 3.65-2.82
(m, 5H, two sets of peaks from two diastereomers), 2.50 (s, 3H),
2.20-2.00 (m, 2H), 1.69 (s, 3H). rhSyk activity=+++.
Example 14
Alternative Preparation of Examples 4 and 3; Preparation of Related
Compounds of Formula I
trans-4-{(1R or
1S)-1-Hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid
(Enantiomer 1, same stereoisomer as Example 4)
##STR00055##
[0337] Step 1:
[0338] To a vial under nitrogen was added palladium acetate (10 mg,
0.045 mmol), butyl di-1-adamantylphosphine (32 mg, 0.090 mmol) and
dioxane (1 mL) and the mixture was stirred for 10 minutes. To a
separate flask was added
6-bromo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine
(75 mg, 0.23 mmol), cesium fluoride (103 mg, 0.68 mmol), pivalic
acid (35 mg, 0.34 mmol) and a solution of butyl trans-4-[(1R or
1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate
(Intermediate 2, Peak 2, R.sub.t=4.14 min) (70 mg, 0.23 mmol) in
dioxane (1 mL). The mixture in flask 1 was added to the mixture in
flask 2 and the resulting mixture was evacuated and then purged 5
times with argon. The mixture was then heated to 100.degree. C. for
24 hours. The mixture was then diluted with ethyl acetate, filtered
through CELITE and the CELITE was washed with ethyl acetate. The
filtrate was concentrated in vacuo and the crude product was
purified by chromatography on silica gel to afford butyl
trans-4-{(1R or
1S)-1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylate. MS ESI
calc'd. for C.sub.28H.sub.34F.sub.3N.sub.4O.sub.3S [M+H].sup.+ 563.
found 563. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 10.18 (s,
1H), 8.65 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 7.34 (s, 1H), 7.19 (t,
J=12.4 Hz, 1H), 7.06 (d, J=16.9 Hz, 1H), 5.76 (s, 1H), 3.95 (t,
J=6.5 Hz, 2H), 2.31 (s, 3H), 2.17-2.05 (m, 1H), 1.96-1.80 (m, 3H),
1.72-1.59 (m, 1H), 1.59-1.44 (m, 5H), 1.35-1.14 (m, 6H), 1.11-0.96
(m, 1H), 0.84 (t, J=7.4 Hz, 3H). rhSyk=++
[0339] Step 2:
[0340] To a microwave vial containing butyl trans-4-{(1R or
1S)-1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylate (76 mg,
0.14 mmol) in methanol (3 mL) was added aqueous sodium hydroxide (1
M in water, 2.0 mL, 2.0 mmol) and the mixture was heated in the
microwave at 140.degree. C. for 60 minutes. The mixture was allowed
to cool to room temperature and acidified with aqueous hydrochloric
acid to a pH 3. The mixture was diluted with ethyl acetate and the
organic layer was separated, dried over magnesium sulfate, filtered
and concentrated to afford trans-4-{(1R or
1S)-1-Hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}py-
ridin-2-yl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid
(Enantiomer 1). MS ESI calc'd. for
C.sub.24H.sub.26F.sub.3N.sub.4O.sub.3S [M+H].sup.+ 507. found 507.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 8.62 (d, J=5.6 Hz, 1H),
8.38 (s, 1H), 7.92 (s, 1H), 7.51 (s, 1H), 7.40 (t, J=16.4 Hz, 1H),
7.05 (s, 1H), 2.50 (s, 3H), 2.24-2.11 (m, 1H), 2.10-1.93 (m, 3H),
1.89-1.76 (m, 1H), 1.66-1.58 (m, 4H), 1.47-1.31 (m, 3H), 1.26-1.11
(m, 1H). rhSyk=+++
[0341] The following compounds were prepared in an analogous manner
of that described in Example 14, step 1, and where appropriate,
step 2 as well. Unless otherwise specified, the terms cis and trans
refer to the stereochemistry around the cycloalkyl ring.
[0342] For compounds 3, compounds 14-1 through 14-10, compounds
14-39 through 14-43 and compounds 14-52 through 14-54, Enantiomer 1
was prepared from Intermediate 2, Peak 2 while Enantiomer 2 was
prepared from Intermediate 2, Peak 1.
[0343] For compounds 14-30 through 14-38 and 14-44 through 14-51,
Isomer 1 was prepared from Intermediate 13, Step 3, Peak 1 while
Isomer 2 was prepared from Intermediate 13, Step 3, Peak 2.
Compound 14-30 was prepared from the diastereomeric mixture from
Intermediate 13, Step 4. Compounds 14-11 through 14,14 were
prepared from Intermediate 12. Compounds 14-15, 14-16, 14-21 and
14-22 were prepared from Example 1, Step 2. Compounds 14-17, 14-18,
14-23 and 14-24 were prepared from Intermediate 8. Compounds 14-19,
14-20, 14-25 and 14-26 were prepared from Intermediate 9. Compounds
14-27 through 14-29 were prepared from Intermediate 10. Compound
14-55 was prepared from Intermediate 15, Step 2. Compound 14-56 was
prepared from Intermediate 15, Step 3.
TABLE-US-00009 ##STR00056## [M + H]+ Ex. R.sup.1/R.sup.2 R.sup.6 R
rhSyk Activity Obs'd Form(s) 3 CF.sub.3/H CH.sub.3 ##STR00057## +++
507 Free Base 14-1 CH.sub.3/H CH.sub.3 ##STR00058## +++ 453 Free
Base 14-2 OCH.sub.3/H CH.sub.3 ##STR00059## ++ 511 Free Base 14-3
OCH.sub.3/H CH.sub.3 ##STR00060## +++ 469 Free Base 14-4
CHF.sub.2/H CH.sub.3 ##STR00061## +++ 489 TFA Salt 14-5 CH.sub.3/Cl
CH.sub.3 ##STR00062## +++ 487 Free Base 14-6 cPr/H CH.sub.3
##STR00063## ++ 535 Free Base 14-7 cPr/H CH.sub.3 ##STR00064## +++
479 Free Base 14-8 iPr/H CH.sub.3 ##STR00065## +++ 481 Free Base
14-9 Me/F CH.sub.3 ##STR00066## +++ 471 Free Base 14-10 Me/F
CH.sub.3 ##STR00067## +++ 471 Free Base 14-11 CF.sub.3/H CH.sub.3
##STR00068## +++ 493 Free Base 14-12 CF.sub.3/H CH.sub.3
##STR00069## +++ 493 Free Base 14-13 CF.sub.3/H CH.sub.3
##STR00070## +++ 493 Free Base 14-14 CF.sub.3/H CH.sub.3
##STR00071## +++ 493 Free Base 14-15 CF.sub.3/H Et ##STR00072## +++
521 HC1 Salt 14-16 CF.sub.3/H Et ##STR00073## +++ 521 HCl Salt
14-17 CF.sub.3/H cPr ##STR00074## +++ 533 TFA Salt 14-18 CF.sub.3/H
cPr ##STR00075## +++ 533 HCl Salt 14-19 CF.sub.3/H CF.sub.3
##STR00076## +++ 561 HCl Salt 14-20 CF.sub.3/H CF.sub.3
##STR00077## +++ 561 HCl Salt 14-21 OiPr/H Et ##STR00078## +++ 511
HCl Salt 14-22 OiPr/H Et ##STR00079## +++ 511 HCl Salt 14-23 OiPr/H
cPr ##STR00080## +++ 523 HCl Salt 14-24 OiPr/H cPr ##STR00081## +++
523 HCl Salt 14-25 OiPr/H CF.sub.3 ##STR00082## +++ 551 HCl Salt
14-26 OiPr/H CF.sub.3 ##STR00083## +++ 551 HCl Salt 14-27
CF.sub.3/H H ##STR00084## +++ 507 Free Base 14-28 CF.sub.3/H H
##STR00085## +++ 493 Free Base 14-29 CF.sub.3/H H ##STR00086## +++
493 Free Base 14-30 CF.sub.3/H CH.sub.3 ##STR00087## +++ 535 TFA
Salt 14-31 CF.sub.3/H CH.sub.3 ##STR00088## +++ 535 Free Base 14-32
CF.sub.3/H CH.sub.3 ##STR00089## +++ 535 Free Base 14-33 CH.sub.3/H
CH.sub.3 ##STR00090## +++ 481 Free Base 14-34 CH.sub.3/H CH.sub.3
##STR00091## +++ 481 Free Base 14-35 OCH.sub.3/H CH.sub.3
##STR00092## +++ 497 TFA Salt 14-36 OCH.sub.3/H CH.sub.3
##STR00093## +++ 497 TFA Salt 14-37 CHF.sub.2/H CH.sub.3
##STR00094## +++ 517 TFA Salt 14-38 CHF.sub.2/H CH.sub.3
##STR00095## +++ 517 Free Base
TABLE-US-00010 ##STR00096## [M + H]+ Ex. R.sup.1/R.sup.2 R.sup.6 R
rhSyk Activity Obs'd Form(s) 14-39 CH.sub.3/H CH.sub.3 ##STR00097##
+++ 439 TFA Salt 14-40 CH.sub.3/H CH.sub.3 ##STR00098## +++ 439 TFA
Salt 14-41 OCH.sub.3/H CH.sub.3 ##STR00099## +++ 455 Free base
14-42 CHF.sub.2/H CH.sub.3 ##STR00100## +++ 475 Free Base 14-43
iPr/H CH.sub.3 ##STR00101## +++ 467 Free Base 14-44 CF.sub.3/H
CH.sub.3 ##STR00102## +++ 521 Free Base 14-45 CF.sub.3/H CH.sub.3
##STR00103## +++ 521 Free Base 14-46 CH.sub.3/H CH.sub.3
##STR00104## +++ 467 Free Base 14-47 CH.sub.3/H CH.sub.3
##STR00105## +++ 467 Free Base 14-48 OCH.sub.3/H CH.sub.3
##STR00106## +++ 483 TFA Salt 14-49 OCH.sub.3/H CH.sub.3
##STR00107## +++ 483 TFA Salt 14-50 CHF.sub.2/H CH.sub.3
##STR00108## +++ 503 Free Base 14-51 CHF.sub.2/H CH.sub.3
##STR00109## +++ 503 Free Base
TABLE-US-00011 ##STR00110## rhSyk [M + H]+ Ex. R.sup.3
Stereochemistry Activity Obs'd Form(s) 14-52 Cl (trans isomer, +++
527 TFA Salt enantiomer 1) 14-53 CHF.sub.2 (trans isomer, +++ 543
TFA Salt enantiomer 1) 14-54 cPr (trans isomer, +++ 533 Free Base
enantiomer 1)
TABLE-US-00012 ##STR00111## rhSyk [M + H]+ Ex. R.sup.5/6 a R
.sup.5/6 b Activity Obs'd Form(s) 14-55 OH CH.sub.3 +++ 464 Free
Base 14-46 CH.sub.3 OH +++ 464 Free Base
Example 15
Stereoisomers of
4-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyr-
idin-2-yl)-1,3-thiazol-2-yl]ethyl}-2-methylcyclohexanecarboxylic
acid
[0344] The following compounds were prepared in an analogous manner
to that described in Example 14, steps 1 and 2 using the products
from Intermediate 14, step 2. During step 2, isomerization
sometimes occurred. When isomerization occurred, the isomers were
separated and then tested. The table below indicates when
isomerization was observed.
TABLE-US-00013 ##STR00112## Isomer- ization Intermediate Ob- [M +
H]+ rhSyk Used served? Ex. Obs'd Activity Form (s) Intermediate 14,
Yes 15-1 521 +++ (Peak 1) Free Base Step 2, Isomer 1 15-2 521 +++
(Peak 2) Free Base Intermediate 14, Yes 15-3 521 +++ (Peak 1) Free
Base Step 2, Isomer 2 15-4 521 +++ (Peak 2) Free Base Intermediate
14, Yes 15-5 521 +++ (Peak 1) TFA Salt Step 2, Isomer 3 15-6 521
+++ (Peak 2) TFA Salt Intermediate 14, Yes 15-7 521 +++ (Peak 1)
Free Base Step 2, Isomer 4 15-8 521 +++ (Peak 2) Free Base
Intermediate 14, No 15-9 521 +++ Free Base Step 2, Isomer 5
Intermediate 14, No 15-10 521 +++ Free Base Step 2, Isomer 6
Intermediate 14, No 15-11 521 +++ Free Base Step 2, Isomer 7
Intermediate 14, No 15-12 521 +++ TFA Salt Step 2, Isomer 8
Intermediate 14, No 15-13 521 +++ TFA Salt Step 2, Isomer 9
Intermediate 14, No 15-14 521 +++ Free Base Step 2, Isomer 10
Intermediate 14, No 15-15 521 +++ Free Base Step 2, Isomer 11
Intermediate 14, No 15-16 521 +++ Free Base Step 2, Isomer 12
Intermediate 14, No 15-17 521 +++ Free Base Step 2, Isomer 13
* * * * *